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1. Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes

Author: Albrechtsen, A, Grarup, N, Li, Y, Sparsø, T, Tian, G, Cao, H, Jiang, T, Kim, SY, Korneliussen, T, Li, Q, Nie, C, Wu, R, Skotte, L, Morris, AP, Ladenvall, C, Cauchi, S, Stančáková, A, Andersen, G, Astrup, A, Banasik, K, Bennett, AJ, Bolund, L, Charpentier, G, Chen, Y, Dekker, JM, Doney, ASF, Dorkhan, M, Forsen, T, Frayling, TM, Groves, CJ, Gui, Y, Hallmans, G, Hattersley, AT, He, K, Hitman, GA, Holmkvist, J, Huang, S, Jiang, H, Jin, X, Justesen, JM, Kristiansen, K, Kuusisto, J, Lajer, M, Lantieri, O, Li, W, Liang, H, Liao, Q, Liu, X, Ma, T, Ma, X, Manijak, MP, Marre, M, Mokrosiński, J, Morris, AD, Mu, B, Nielsen, AA, Nijpels, G, Nilsson, P, Palmer, CNA, Rayner, NW, Renström, F, Ribel-Madsen, R, Robertson, N, Rolandsson, O, Rossing, P, Schwartz, TW, Slagboom, PE, Sterner, M, D.E.S.I.R. Study Group, Tang, M, Tarnow, L, the DIAGRAM Consortium, Tuomi, T, van’t Riet, E, van Leeuwen, N, Varga, TV, Vestmar, MA, Walker, M, Wang, B, Wang, Y, Wu, H, Xi, F, Yengo, L, Yu, C, Zhang, X, Zhang, J, Zhang, Q, Zhang, W, Zheng, H, Zhou, Y, Altshuler, D, ‘t Hart, LM, Franks, PW, Balkau, B, Froguel, P, McCarthy, MI, Laakso, M, Groop, L, Christensen, C, and Brandslund, I
Subjects: Diabetes, Human Genome, Nutrition, Genetics, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Diabetes Mellitus, Type 2, Exome, Gene Frequency, Genotype, High-Throughput Nucleotide Sequencing, Humans, Hypertension, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Exome sequencing, Genetic epidemiology, Lipids, Next-generation sequencing, Obesity, Type 2 diabetes, D.E.S.I.R. Study Group, DIAGRAM Consortium, Clinical Sciences, Paediatrics and Reproductive Medicine, Public Health and Health Services, Endocrinology & Metabolism
Abstract: Aims/hypothesisHuman complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes.MethodsThe study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p 1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10(-10)).Conclusions/interpretationWe applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.
Published: 2013

2. Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes

Author: Skotte, L, Fadista, J, Bybjerg-Grauholm, J, Appadurai, V, Hildebrand, MS, Hansen, TF, Banasik, K, Grove, J, Albinana, C, Geller, F, Bjurstrom, CF, Vilhjalmsson, BJ, Coleman, M, Damiano, JA, Burgess, R, Scheffer, IE, Pedersen, OBV, Erikstrup, C, Westergaard, D, Nielsen, KR, Sorensen, E, Bruun, MT, Liu, X, Hjalgrim, H, Pers, TH, Mortensen, PB, Mors, O, Nordentoft, M, Dreier, JW, Borglum, AD, Christensen, J, Hougaard, DM, Buil, A, Hviid, A, Melbye, M, Ullum, H, Berkovic, SF, Werge, T, Feenstra, B, Skotte, L, Fadista, J, Bybjerg-Grauholm, J, Appadurai, V, Hildebrand, MS, Hansen, TF, Banasik, K, Grove, J, Albinana, C, Geller, F, Bjurstrom, CF, Vilhjalmsson, BJ, Coleman, M, Damiano, JA, Burgess, R, Scheffer, IE, Pedersen, OBV, Erikstrup, C, Westergaard, D, Nielsen, KR, Sorensen, E, Bruun, MT, Liu, X, Hjalgrim, H, Pers, TH, Mortensen, PB, Mors, O, Nordentoft, M, Dreier, JW, Borglum, AD, Christensen, J, Hougaard, DM, Buil, A, Hviid, A, Melbye, M, Ullum, H, Berkovic, SF, Werge, T, and Feenstra, B
Abstract: Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy. We conducted a genome-wide association study of febrile seizures in 7635 cases and 83 966 controls identifying and replicating seven new loci, all with P < 5 × 10-10. Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10, and four other loci harboured genes (BSN, ERC2, GABRG2, HERC1) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. Four previously reported loci (SCN1A, SCN2A, ANO3 and 12q21.33) were all confirmed. Collectively, the seven novel and four previously reported loci explained 2.8% of the variance in liability to febrile seizures, and the single nucleotide polymorphism heritability based on all common autosomal single nucleotide polymorphisms was 10.8%. GABRG2, SCN1A and SCN2A are well-established epilepsy genes and, overall, we found positive genetic correlations with epilepsies (rg = 0.39, P = 1.68 × 10-4). Further, we found that higher polygenic risk scores for febrile seizures were associated with epilepsy and with history of hospital admission for febrile seizures. Finally, we found that polygenic risk of febrile seizures was lower in febrile seizure patients with neuropsychiatric disease compared to febrile seizure patients in a general population sample. In conclusion, this largest genetic investigation of febrile seizures to date implicates central fever response genes as well as genes affecting neuronal excitability, including several known epilepsy genes. Further functional and genetic studies based on these findings will provide important insights into the complex pathophysiological processes of seizures with and without fever.
Published: 2022

3. Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women

Author: Steinthorsdottir, V. (Valgerdur), McGinnis, R. (Ralph), Williams, N. O. (Nicholas O.), Stefansdottir, L. (Lilja), Thorleifsson, G. (Gudmar), Shooter, S. (Scott), Fadista, J. (Joao), Sigurdsson, J. K. (Jon K.), Auro, K. M. (Kirsi M.), Berezina, G. (Galina), Borges, M.-C. (Maria-Carolina), Bumpstead, S. (Suzannah), Bybjerg-Grauholm, J. (Jonas), Colgiu, I. (Irina), Dolby, V. A. (Vivien A.), Dudbridge, F. (Frank), Engel, S. M. (Stephanie M.), Franklin, C. S. (Christopher S.), Frigge, M. L. (Michael L.), Frisbaek, Y. (Yr), Geirsson, R. T. (Reynir T.), Geller, F. (Frank), Gretarsdottir, S. (Solveig), Gudbjartsson, D. F. (Daniel F.), Harmon, Q. (Quaker), Hougaard, D. M. (David Michael), Hegay, T. (Tatyana), Helgadottir, A. (Anna), Hjartardottir, S. (Sigrun), Jaeaeskelaeinen, T. (Tiina), Johannsdottir, H. (Hrefna), Jonsdottir, I. (Ingileif), Juliusdottir, T. (Thorhildur), Kalsheker, N. (Noor), Kasimov, A. (Abdumadjit), Kemp, J. P. (John P.), Kivinen, K. (Katja), Klungsoyr, K. (Kari), Lee, W. K. (Wai K.), Melbye, M. (Mads), Miedzybrodska, Z. (Zosia), Moffett, A. (Ashley), Najmutdinova, D. (Dilbar), Nishanova, F. (Firuza), Olafsdottir, T. (Thorunn), Perola, M. (Markus), Pipkin, F. B. (Fiona Broughton), Poston, L. (Lucilla), Prescott, G. (Gordon), Saevarsdottir, S. (Saedis), Salimbayeva, D. (Damilya), Scaife, P. J. (Paula Juliet), Skotte, L. (Line), Staines-Urias, E. (Eleonora), Stefansson, O. A. (Olafur A.), Sorensen, K. M. (Karina Meden), Thomsen, L. C. (Liv Cecilie Vestrheim), Tragante, V. (Vinicius), Trogstad, L. (Lill), Simpson, N. A. (Nigel A. B.), Laivuori, H. (Hannele), Morgan, L. (Linda), Aripova, T. (Tamara), Casas, J. P. (Juan P.), Dominiczak, A. F. (Anna F.), Walker, J. J. (James J.), Thorsteinsdottir, U. (Unnur), Iversen, A.-C. (Ann-Charlotte), Feenstra, B. (Bjarke), Lawlor, D. A. (Deborah A.), Boyd, H. A. (Heather Allison), Magnus, P. (Per), Zakhidova, N. (Nodira), Svyatova, G. (Gulnara), Stefansson, K. (Kari), Heinonen, S. (Seppo), Kajantie, E. (Eero), Kere, J. (Juha), Pouta, A. (Anneli), Macphail, S. (Sheila), Kilby, M. (Mark), Habiba, M. (Marwan), Williamson, C. (Catherine), O'Shaughnessy, K. (Kevin), O'Brien, S. (Shaughn), Cameron, A. (Alan), Redman, C. W. (Christopher W. G.), Farrall, M. (Martin), and Caulfield, M. (Mark)
Subjects: embryonic structures, reproductive and urinary physiology, female genital diseases and pregnancy complications
Abstract: Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia. Studies to identify maternal variants associated with preeclampsia have been limited by sample size. Here, the authors meta-analyze eight GWAS of 9,515 preeclamptic women, identifying five variants associated with preeclampsia and showing that genetic predisposition to hypertension is a major risk factor for preeclampsia.
Published: 2020

4. Genome-wide study identifies association between HLA-B∗55:01 and Self-Reported Penicillin Allergy

Author: Krebs, K., Bovijn, J., Zheng, N., Lepamets, M., Censin, J.C., Jürgenson, T., Särg, D., Abner, E., Laisk, T., Luo, Y., Skotte, L., Geller, F., Feenstra, B., Wang, W., Auton, A., Raychaudhuri, S., Esko, T., Metspalu, A., Laur, S., Roden, D.M., Wei, W-Q, Holmes, M.V., Lindgren, C.M., Phillips, E.J., Mägi, R., Milani, L., Fadista, J., Agee, M., Aslibekyan, S., Bell, R.K., Bryc, K., Clark, S.K., Elson, S.L., Fletez-Brant, K., Fontanillas, P., Furlotte, N.A., Gandhi, P.M., Heilbron, K., Hicks, B., Hinds, D.A., Huber, K.E., Jewett, E.M., Jiang, Y., Kleinman, A., Lin, K-H, Litterman, N.K., Luff, M.K., McCreight, J.C., McIntyre, M.H., McManus, K.F., Mountain, J.L., Mozaffari, S.V., Nandakumar, P., Noblin, E.S., Northover, C.A.M., O’Connell, J., Petrakovitz, A.A., Pitts, S.J., Poznik, G.D., Sathirapongsasuti, J.F., Shastri, A.J., Shelton, J.F., Shringarpure, S., Tian, C., Tung, J.Y., Tunney, R.J., Vacic, V., Wang, X., Zare, A.S., Krebs, K., Bovijn, J., Zheng, N., Lepamets, M., Censin, J.C., Jürgenson, T., Särg, D., Abner, E., Laisk, T., Luo, Y., Skotte, L., Geller, F., Feenstra, B., Wang, W., Auton, A., Raychaudhuri, S., Esko, T., Metspalu, A., Laur, S., Roden, D.M., Wei, W-Q, Holmes, M.V., Lindgren, C.M., Phillips, E.J., Mägi, R., Milani, L., Fadista, J., Agee, M., Aslibekyan, S., Bell, R.K., Bryc, K., Clark, S.K., Elson, S.L., Fletez-Brant, K., Fontanillas, P., Furlotte, N.A., Gandhi, P.M., Heilbron, K., Hicks, B., Hinds, D.A., Huber, K.E., Jewett, E.M., Jiang, Y., Kleinman, A., Lin, K-H, Litterman, N.K., Luff, M.K., McCreight, J.C., McIntyre, M.H., McManus, K.F., Mountain, J.L., Mozaffari, S.V., Nandakumar, P., Noblin, E.S., Northover, C.A.M., O’Connell, J., Petrakovitz, A.A., Pitts, S.J., Poznik, G.D., Sathirapongsasuti, J.F., Shastri, A.J., Shelton, J.F., Shringarpure, S., Tian, C., Tung, J.Y., Tunney, R.J., Vacic, V., Wang, X., and Zare, A.S.
Abstract: Hypersensitivity reactions to drugs are often unpredictable and can be life threatening, underscoring a need for understanding their underlying mechanisms and risk factors. The extent to which germline genetic variation influences the risk of commonly reported drug allergies such as penicillin allergy remains largely unknown. We extracted data from the electronic health records of more than 600,000 participants from the UK, Estonian, and Vanderbilt University Medical Center’s BioVU biobanks to study the role of genetic variation in the occurrence of self-reported penicillin hypersensitivity reactions. We used imputed SNP to HLA typing data from these cohorts to further fine map the human leukocyte antigen (HLA) association and replicated our results in 23andMe’s research cohort involving a total of 1.12 million individuals. Genome-wide meta-analysis of penicillin allergy revealed two loci, including one located in the HLA region on chromosome 6. This signal was further fine-mapped to the HLA-B∗55:01 allele (OR 1.41 95% CI 1.33–1.49, p value 2.04 × 10−31) and confirmed by independent replication in 23andMe’s research cohort (OR 1.30 95% CI 1.25–1.34, p value 1.00 × 10−47). The lead SNP was also associated with lower lymphocyte counts and in silico follow-up suggests a potential effect on T-lymphocytes at HLA-B∗55:01. We also observed a significant hit in PTPN22 and the GWAS results correlated with the genetics of rheumatoid arthritis and psoriasis. We present robust evidence for the role of an allele of the major histocompatibility complex (MHC) I gene HLA-B in the occurrence of penicillin allergy.
Published: 2020

5. Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration

Author: Liu, X.P., Helenius, D., Skotte, L., Beaumont, RN, Wielscher, M., Geller, F. (Frank), Liu, X.P., Helenius, D., Skotte, L., Beaumont, RN, Wielscher, M., and Geller, F. (Frank)
Abstract: The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10−14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in proinflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality
Published: 2019
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6. Associations of autozygosity with a broad range of human phenotypes

Author: Clark, D.W. (David W), Okada, Y. (Yukinori), Moore, K.H.S. (Kristjan H S), Mason, D. (Dan), Pirastu, N. (Nicola), Gandin, I. (Ilaria), Mattsson, H. (Hannele), Barnes, C.L.K. (Catriona L K), Lin, K. (Kuang), Zhao, J.H. (Jing Hua), Deelen, P. (Patrick), Rohde, R. (Rebecca), Schurmann, C. (Claudia), Guo, X. (Xiuqing), Giulianini, F. (Franco), Zhang, W. (Weihua), Medina-Gomez, M.C. (Carolina), Karlsson, R. (Robert), Bao, Y. (Yanchun), Bartz, T.M. (Traci M), Baumbach, C. (Clemens), Biino, G. (Ginevra), Bixley, M.J. (Matthew J), Brumat, M. (Marco), Chai, J.-F. (Jin-Fang), Corre, T. (Tanguy), Cousminer, D.L. (Diana), Dekker, A.M. (Annelot M), Eccles, D.A. (David A), Eijk, K.R. (Kristel) van, Fuchsberger, C. (Christian), Gao, H. (He), Germain, M. (Marine), Gordon, S.D. (Scott D.), de Haan, H.G. (Hugoline G), Harris, S.E. (Sarah), Hofer, E. (Edith), Huerta-Chagoya, A. (Alicia), Igartua, C. (Catherine), Jansen, I. (Iris), Jia, Y. (Yucheng), Kacprowski, T. (Tim), Karlsson, T. (Torgny), Kleber, M.E. (Marcus), Li, S.A. (Shengchao Alfred), Li-Gao, R. (Ruifang), Mahajan, A. (Anubha), Matsuda, K. (Koichi), Meidtner, K. (Karina), Meng, W. (Weihua), Montasser, M.E. (May E.), Most, P.J. (Peter) van der, Munz, M. (Matthias), Nutile, T. (Teresa), Palviainen, T. (Teemu), Prasad, G. (Gauri), Prasad, R.B. (Rashmi B), Priyanka, T.D.S. (Tallapragada Divya Sri), Rizzi, F. (Federica), Salvi, E. (Erika), Sapkota, B.R. (Bishwa R), Shriner, D. (Daniel), Skotte, L. (Line), Smart, M.C. (Melissa C), Smith, A.V. (Albert), Spek, A. (Ashley) van der, Spracklen, C.N. (Cassandra N), Strawbridge, R.J. (Rona), Tajuddin, S.M. (Salman M), Trompet, S. (Stella), Turman, C. (Constance), Verweij, N. (Niek), Viberti, C. (Clara), Wang, L. (Lihua), Warren, H. (Helen), Wootton, R.E. (Robyn E), Yanek, L.R. (Lisa), Yao, J. (Jie), Yousri, N.A. (Noha A), Zhao, W. (Wei), Adeyemo, A.A. (Adebowale A), Afaq, S. (Saima), Aguilar-Salinas, C.A. (Carlos Alberto), Akiyama, M. (Masato), Albert, M.L. (Matthew L), Allison, M.A. (Matthew A), Alver, M. (Maris), Aung, T. (Tin), Azizi, J. (Joshan), Bentley, A.R. (Amy), Boeing, H. (Heiner), Boerwinkle, E.A. (Eric), Borja, J.B. (Judith B), Borst, G.J. (Gert) de, Bottinger, E.P. (Erwin), Broer, L. (Linda), Campbell, H. (Harry), Chanock, S.J. (Stephen), Chee, M.-L. (Miao-Li), Chen, G. (Guanjie), Chen, Y.-D.I. (Yii-Der I), Chen, Z. (Zhengming), Chiu, Y.-F. (Yen-Feng), Cocca, M. (Massimiliano), Collins, F.S. (Francis), Concas, M.P. (Maria Pina), Corley, J. (Janie), Cugliari, G. (Giovanni), Dam, R.M. (Rob) van, Damulina, A. (Anna), Daneshpour, M.S. (Maryam S), Day, F.R. (Felix), Delgado, G., Dhana, K. (Klodian), Doney, A.S.F. (Alex), Dörr, M. (Marcus), Doumatey, A. (Ayo), Dzimiri, N. (Nduna), Ebenesersdóttir, S.S. (S Sunna), Elliott, J. (Joshua), Elliott, P. (Paul), Ewert, R. (Ralf), Felix, J.F. (Janine), Fischer, K. (Krista), Freedman, B.I. (Barry), Girotto, S., Goel, A. (Anuj), Gögele, M. (Martin), Goodarzi, M. (Mark), Graff, M.J. (Maud J.L.), Granot-Hershkovitz, E. (Einat), Grodstein, F. (Francine), Guarrera, S. (Simonetta), Gudbjartsson, D.F. (Daniel), Guity, K. (Kamran), Gunnarsson, B. (Bjarni), Guo, Y. (Yu), Hagenaars, S.P. (Saskia P), Haiman, C.A. (Christopher), Halevy, A. (Avner), Harris, T.B. (Tamara B), Hedayati, M. (Mehdi), Heel, D.A. (David) van, Hirata, M. (Makoto), Höfer, I. (Imo), Hsiung, C.A. (Chao Agnes), Huang, J. (Jinyan), Hung, Y.-J. (Yi-Jen), Ikram, M.A. (Arfan), Jagadeesan, A. (Anuradha), Jousilahti, P. (Pekka), Kamatani, Y. (Yoichiro), Kanai, M. (Masahiro), Kerrison, N.D. (Nicola D), Kessler, T. (Thorsten), Khaw, K.-T. (Kay-Tee), Khor, C.C., Kleijn, D.P.V. (Dominique) de, Koh, W.-P. (Woon-Puay), Kolcic, I. (Ivana), Kraft, P. (Peter), Krämer, B.K. (Bernhard), Kutalik, Z. (Zoltán), Kuusisto, J. (Johanna), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Lawlor, D.A. (Debbie), Lee, I.-T. (I-Te), Lee, W.-J. (Wen-Jane), Lerch, M. (M.), Li, L. (Liming), Liu, J. (Jianjun), Loh, M. (Marie), London, S.J. (Stephanie J), Loomis, S.J. (Stephanie J.), Lu, Y. (Yingchang), Luan, J. (Jian’an), Mägi, R. (Reedik), Manichaikul, A.W. (Ani W), Manunta, P. (Paolo), Masson, G. (Gisli), Matoba, N. (Nana), Mei, X.W. (Xue W), Meisinger, C. (Christa), Meitinger, T. (Thomas), Mezzavilla, M. (Massimo), Milani, L. (Lili), Millwood, I.Y. (Iona), Momozawa, Y. (Yukihide), Moore, A. (Amy), Morange, P.-E. (P.), Moreno-Macías, H. (Hortensia), Mori, T.A. (Trevor A), Morrison, A.C. (Alanna), Muka, T. (Taulant), Murakami, Y. (Yoshinori), Murray, A.D. (Alison D), Mutsert, R. (Reneé) de, Mychaleckyj, J.C. (Josyf), Nalls, M.A. (Michael), Nauck, M. (Matthias), Neville, M.J. (Matthew), Nolte, I.M. (Ilja), Ong, K.K. (Ken K), Orozco, L. (Lorena), Padmanabhan, S. (Sandosh), Pálsson, G. (Gunnar), Palmer, C.N.A. (Colin), Penninx, B.W.J.H., Pattie, A. (Alison), Polasek, O. (Ozren), Poulter, N.R. (Neil), Pramstaller, P.P. (Peter P), Quintana-Murci, L. (Lluis), Räikkönen, K. (Katri), Ralhan, S. (Sarju), Rao, D.C. (Dabeeru C), Rheenen, W. (Wouter) van, Rich, S.S. (Stephen), Ridker, P.M. (Paul M), Rietveld, C.A. (Cornelius A), Robino, A. (Antonietta), Rooij, F.J.A. (Frank) van, Ruggiero, D., Saba, Y. (Yasaman), Sabanayagam, C. (Charumathi), Sabater-Lleal, M. (Maria), Sala, C. (Cinzia), Salomaa, V. (Veikko), Sandow, K. (Kevin), Schmidt, H. (Helena), Scott, L.J. (Laura J), Scott, W.R. (William R), Sedaghati-Khayat, B. (Bahareh), Sennblad, B. (Bengt), Setten, J. (Jessica) van, Sever, P.J. (Peter J), Sheu, W.H.-H. (Wayne H-H), Shi, Y. (Yuan), Shrestha, S. (Smeeta), Shukla, S.R. (Sharvari Rahul), Sigurdsson, J.K. (Jon K), Sikka, T.T. (Timo Tonis), Singh, J.R. (Jai Rup), Smith, B.H. (Blair), Stancáková, A. (Alena), Stanton, A. (Alice), Starr, J.M. (John), Stefansdottir, L. (Lilja), Straker, L. (Leon), Sulem, P. (Patrick), Sveinbjornsson, G. (Gardar), Swertz, M.A. (Morris A), Taylor, A.M. (Adele M), Taylor, K.D. (Kent), Terzikhan, N. (Natalie), Tham, Y.-C. (Yih-Chung), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tillander, A. (Annika), Tracy, R.P. (Russell), Tusié-Luna, T. (Teresa), Tzoulaki, I., Vaccargiu, S. (Simona), Vangipurapu, J. (Jagadish), Veldink, J.H. (Jan), Vitart, V. (Veronique), Völker, U. (Uwe), Vuoksimaa, E. (Eero), Wakil, S.M. (Salma M), Waldenberger, M. (Melanie), Wander, G.S. (Gurpreet S), Wang, Y.X. (Ya Xing), Wareham, N.J. (Nick), Wild, S.H. (Sarah), Yajnik, C.S. (Chittaranjan S), Yuan, J.-M. (Jian-Min), Zeng, L. (Lingyao), Zhang, L. (Liang), Zhou, J. (Jie), Amin, N. (Najaf), Asselbergs, F.W. (Folkert), Bakker, S.J.L. (Stephan), Becker, D.M. (Diane), Lehne, B. (Benjamin), Bennett, D.A. (David), Berg, L.H. (Leonard) van den, Berndt, S.I. (Sonja), Bharadwaj, D. (Dwaipayan), Bielak, L.F. (Lawrence F.), Bochud, M. (Murielle), Boehnke, M. (Michael), Bouchard, C. (Claude), Bradfield, J.P. (Jonathan), Brody, J.A. (Jennifer A), Campbell, A. (Archie), Carmi, S. (Shai), Caulfield, M. (Mark), Cesarini, D. (David), Chambers, J.C. (John C), Chandak, G.R. (Giriraj), Cheng, C.-Y. (Ching-Yu), Ciullo, M. (Marina), Warrington, N.M. (Nicole), Cusi, D. (Daniele), Smith, G.D. (George Davey), Deary, I.J. (Ian J), Dorajoo, R. (Rajkumar), Duijn, C.M. (Cornelia) van, Ellinghaus, D. (David), Erdmann, J. (Jeanette), Hagen, K. (Knut), Evangelou, E. (Evangelos), Evans, M.K. (Michele), Faul, J.D. (Jessica D), Feenstra, B. (Bjarke), Feitosa, M.F. (Mary Furlan), Foisy, S. (Sylvain), Franke, A. (Andre), Friedlander, Y. (Yechiel), Gasparini, P. (Paolo), Gieger, C. (Christian), Gonzalez, C. (Clicerio), Goyette, P. (Philippe), Grant, S.F.A. (Struan), Griffiths, L.R. (Lyn R), Groop, L. (Leif), Gudnason, V. (Vilmundur), Gyllensten, U. (Ulf), Hakonarson, H. (Hakon), Hamsten, A. (Anders), Harst, P. (Pim) van der, Heng, C.K. (Chew-Kiat), Hicks, A.A. (Andrew A), Hochner, H., Huikuri, H.V. (Heikki), Hunt, S.C. (Steven), Jaddoe, V.W.V. (Vincent), De Jager, P., Johannesson, M. (Magnus), Johansson, A. (Åsa), Jonas, J.B. (Jost B), Jukema, J.W. (Jan Wouter), Junttila, M.J. (Juhani), Kaprio, J. (Jaakko), Kardia, S.L.R. (Sharon), Karpe, F. (Fredrik), Kumari, M. (Meena), Laakso, M. (Markku), van der Laan, S.W. (Sander W), Lahti, J. (Jari), Laudes, M. (Matthias), Lea, R.A. (Rodney A), Lieb, W. (Wolfgang), Lumley, T. (Thomas), Martin, N.G. (Nicholas), Ye, S. (Shu), Matullo, G., McCarthy, M.I. (Mark), Medland, S.E. (Sarah), Merriman, A., Metspalu, A. (Andres), Meyer, B.F. (Brian F), Mohlke, K.L. (Karen L), Montgomery, G.W. (Grant), Mook-Kanamori, D. (Dennis), Munroe, P. (Patricia), North, K.E. (Kari), Nyholt, D.R. (Dale), O’connell, J.R. (Jeffery R), Ober, C. (Carole), Oldehinkel, A.J. (Albertine), Palmas, W. (Walter), Pasterkamp, G.G. (Gerard G), Patin, E. (Etienne), Pennell, C.E. (Craig), Perusse, L. (Louis), Peyser, P.A. (Patricia A.), Pirastu, M. (Mario), Polderman, T.J.C. (Tinca), Porteous, D.J. (David J.), Posthuma, D. (Danielle), Psaty, B.M. (Bruce M), Rioux, J.D. 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(Scott D.), de Haan, H.G. (Hugoline G), Harris, S.E. (Sarah), Hofer, E. (Edith), Huerta-Chagoya, A. (Alicia), Igartua, C. (Catherine), Jansen, I. (Iris), Jia, Y. (Yucheng), Kacprowski, T. (Tim), Karlsson, T. (Torgny), Kleber, M.E. (Marcus), Li, S.A. (Shengchao Alfred), Li-Gao, R. (Ruifang), Mahajan, A. (Anubha), Matsuda, K. (Koichi), Meidtner, K. (Karina), Meng, W. (Weihua), Montasser, M.E. (May E.), Most, P.J. (Peter) van der, Munz, M. (Matthias), Nutile, T. (Teresa), Palviainen, T. (Teemu), Prasad, G. (Gauri), Prasad, R.B. (Rashmi B), Priyanka, T.D.S. (Tallapragada Divya Sri), Rizzi, F. (Federica), Salvi, E. (Erika), Sapkota, B.R. (Bishwa R), Shriner, D. (Daniel), Skotte, L. (Line), Smart, M.C. (Melissa C), Smith, A.V. (Albert), Spek, A. (Ashley) van der, Spracklen, C.N. (Cassandra N), Strawbridge, R.J. (Rona), Tajuddin, S.M. (Salman M), Trompet, S. (Stella), Turman, C. (Constance), Verweij, N. (Niek), Viberti, C. (Clara), Wang, L. (Lihua), Warren, H. (Helen), Wootton, R.E. (Robyn E), Yanek, L.R. (Lisa), Yao, J. (Jie), Yousri, N.A. (Noha A), Zhao, W. (Wei), Adeyemo, A.A. (Adebowale A), Afaq, S. (Saima), Aguilar-Salinas, C.A. (Carlos Alberto), Akiyama, M. (Masato), Albert, M.L. (Matthew L), Allison, M.A. (Matthew A), Alver, M. (Maris), Aung, T. (Tin), Azizi, J. (Joshan), Bentley, A.R. (Amy), Boeing, H. (Heiner), Boerwinkle, E.A. (Eric), Borja, J.B. (Judith B), Borst, G.J. (Gert) de, Bottinger, E.P. (Erwin), Broer, L. (Linda), Campbell, H. (Harry), Chanock, S.J. (Stephen), Chee, M.-L. (Miao-Li), Chen, G. (Guanjie), Chen, Y.-D.I. (Yii-Der I), Chen, Z. (Zhengming), Chiu, Y.-F. (Yen-Feng), Cocca, M. (Massimiliano), Collins, F.S. (Francis), Concas, M.P. (Maria Pina), Corley, J. (Janie), Cugliari, G. (Giovanni), Dam, R.M. (Rob) van, Damulina, A. (Anna), Daneshpour, M.S. (Maryam S), Day, F.R. (Felix), Delgado, G., Dhana, K. (Klodian), Doney, A.S.F. (Alex), Dörr, M. (Marcus), Doumatey, A. (Ayo), Dzimiri, N. (Nduna), Ebenesersdóttir, S.S. (S Sunna), Elliott, J. (Joshua), Elliott, P. (Paul), Ewert, R. (Ralf), Felix, J.F. (Janine), Fischer, K. (Krista), Freedman, B.I. (Barry), Girotto, S., Goel, A. (Anuj), Gögele, M. (Martin), Goodarzi, M. (Mark), Graff, M.J. (Maud J.L.), Granot-Hershkovitz, E. (Einat), Grodstein, F. (Francine), Guarrera, S. (Simonetta), Gudbjartsson, D.F. (Daniel), Guity, K. (Kamran), Gunnarsson, B. (Bjarni), Guo, Y. (Yu), Hagenaars, S.P. (Saskia P), Haiman, C.A. (Christopher), Halevy, A. (Avner), Harris, T.B. (Tamara B), Hedayati, M. (Mehdi), Heel, D.A. (David) van, Hirata, M. (Makoto), Höfer, I. (Imo), Hsiung, C.A. (Chao Agnes), Huang, J. (Jinyan), Hung, Y.-J. (Yi-Jen), Ikram, M.A. (Arfan), Jagadeesan, A. (Anuradha), Jousilahti, P. (Pekka), Kamatani, Y. (Yoichiro), Kanai, M. (Masahiro), Kerrison, N.D. (Nicola D), Kessler, T. (Thorsten), Khaw, K.-T. (Kay-Tee), Khor, C.C., Kleijn, D.P.V. (Dominique) de, Koh, W.-P. (Woon-Puay), Kolcic, I. (Ivana), Kraft, P. (Peter), Krämer, B.K. (Bernhard), Kutalik, Z. (Zoltán), Kuusisto, J. (Johanna), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Lawlor, D.A. (Debbie), Lee, I.-T. (I-Te), Lee, W.-J. (Wen-Jane), Lerch, M. (M.), Li, L. (Liming), Liu, J. (Jianjun), Loh, M. (Marie), London, S.J. (Stephanie J), Loomis, S.J. (Stephanie J.), Lu, Y. (Yingchang), Luan, J. (Jian’an), Mägi, R. (Reedik), Manichaikul, A.W. (Ani W), Manunta, P. (Paolo), Masson, G. (Gisli), Matoba, N. (Nana), Mei, X.W. (Xue W), Meisinger, C. (Christa), Meitinger, T. (Thomas), Mezzavilla, M. (Massimo), Milani, L. (Lili), Millwood, I.Y. (Iona), Momozawa, Y. (Yukihide), Moore, A. (Amy), Morange, P.-E. (P.), Moreno-Macías, H. (Hortensia), Mori, T.A. (Trevor A), Morrison, A.C. (Alanna), Muka, T. (Taulant), Murakami, Y. (Yoshinori), Murray, A.D. (Alison D), Mutsert, R. (Reneé) de, Mychaleckyj, J.C. (Josyf), Nalls, M.A. (Michael), Nauck, M. (Matthias), Neville, M.J. (Matthew), Nolte, I.M. (Ilja), Ong, K.K. (Ken K), Orozco, L. (Lorena), Padmanabhan, S. (Sandosh), Pálsson, G. (Gunnar), Palmer, C.N.A. (Colin), Penninx, B.W.J.H., Pattie, A. (Alison), Polasek, O. (Ozren), Poulter, N.R. (Neil), Pramstaller, P.P. (Peter P), Quintana-Murci, L. (Lluis), Räikkönen, K. (Katri), Ralhan, S. (Sarju), Rao, D.C. (Dabeeru C), Rheenen, W. (Wouter) van, Rich, S.S. (Stephen), Ridker, P.M. (Paul M), Rietveld, C.A. (Cornelius A), Robino, A. (Antonietta), Rooij, F.J.A. (Frank) van, Ruggiero, D., Saba, Y. (Yasaman), Sabanayagam, C. (Charumathi), Sabater-Lleal, M. (Maria), Sala, C. (Cinzia), Salomaa, V. (Veikko), Sandow, K. (Kevin), Schmidt, H. (Helena), Scott, L.J. (Laura J), Scott, W.R. (William R), Sedaghati-Khayat, B. (Bahareh), Sennblad, B. (Bengt), Setten, J. (Jessica) van, Sever, P.J. (Peter J), Sheu, W.H.-H. (Wayne H-H), Shi, Y. (Yuan), Shrestha, S. (Smeeta), Shukla, S.R. (Sharvari Rahul), Sigurdsson, J.K. (Jon K), Sikka, T.T. (Timo Tonis), Singh, J.R. (Jai Rup), Smith, B.H. (Blair), Stancáková, A. (Alena), Stanton, A. (Alice), Starr, J.M. (John), Stefansdottir, L. (Lilja), Straker, L. (Leon), Sulem, P. (Patrick), Sveinbjornsson, G. (Gardar), Swertz, M.A. (Morris A), Taylor, A.M. (Adele M), Taylor, K.D. (Kent), Terzikhan, N. (Natalie), Tham, Y.-C. (Yih-Chung), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tillander, A. (Annika), Tracy, R.P. (Russell), Tusié-Luna, T. (Teresa), Tzoulaki, I., Vaccargiu, S. (Simona), Vangipurapu, J. (Jagadish), Veldink, J.H. (Jan), Vitart, V. (Veronique), Völker, U. (Uwe), Vuoksimaa, E. (Eero), Wakil, S.M. (Salma M), Waldenberger, M. (Melanie), Wander, G.S. (Gurpreet S), Wang, Y.X. (Ya Xing), Wareham, N.J. (Nick), Wild, S.H. (Sarah), Yajnik, C.S. (Chittaranjan S), Yuan, J.-M. (Jian-Min), Zeng, L. (Lingyao), Zhang, L. (Liang), Zhou, J. (Jie), Amin, N. (Najaf), Asselbergs, F.W. (Folkert), Bakker, S.J.L. (Stephan), Becker, D.M. (Diane), Lehne, B. (Benjamin), Bennett, D.A. (David), Berg, L.H. (Leonard) van den, Berndt, S.I. (Sonja), Bharadwaj, D. (Dwaipayan), Bielak, L.F. (Lawrence F.), Bochud, M. (Murielle), Boehnke, M. (Michael), Bouchard, C. (Claude), Bradfield, J.P. (Jonathan), Brody, J.A. (Jennifer A), Campbell, A. (Archie), Carmi, S. (Shai), Caulfield, M. (Mark), Cesarini, D. (David), Chambers, J.C. (John C), Chandak, G.R. (Giriraj), Cheng, C.-Y. (Ching-Yu), Ciullo, M. (Marina), Warrington, N.M. (Nicole), Cusi, D. (Daniele), Smith, G.D. (George Davey), Deary, I.J. (Ian J), Dorajoo, R. (Rajkumar), Duijn, C.M. (Cornelia) van, Ellinghaus, D. (David), Erdmann, J. (Jeanette), Hagen, K. (Knut), Evangelou, E. (Evangelos), Evans, M.K. (Michele), Faul, J.D. (Jessica D), Feenstra, B. (Bjarke), Feitosa, M.F. (Mary Furlan), Foisy, S. (Sylvain), Franke, A. (Andre), Friedlander, Y. (Yechiel), Gasparini, P. (Paolo), Gieger, C. (Christian), Gonzalez, C. (Clicerio), Goyette, P. (Philippe), Grant, S.F.A. (Struan), Griffiths, L.R. (Lyn R), Groop, L. (Leif), Gudnason, V. (Vilmundur), Gyllensten, U. (Ulf), Hakonarson, H. (Hakon), Hamsten, A. (Anders), Harst, P. (Pim) van der, Heng, C.K. (Chew-Kiat), Hicks, A.A. (Andrew A), Hochner, H., Huikuri, H.V. (Heikki), Hunt, S.C. (Steven), Jaddoe, V.W.V. (Vincent), De Jager, P., Johannesson, M. (Magnus), Johansson, A. (Åsa), Jonas, J.B. (Jost B), Jukema, J.W. (Jan Wouter), Junttila, M.J. (Juhani), Kaprio, J. (Jaakko), Kardia, S.L.R. (Sharon), Karpe, F. (Fredrik), Kumari, M. (Meena), Laakso, M. (Markku), van der Laan, S.W. (Sander W), Lahti, J. (Jari), Laudes, M. (Matthias), Lea, R.A. (Rodney A), Lieb, W. (Wolfgang), Lumley, T. (Thomas), Martin, N.G. (Nicholas), Ye, S. (Shu), Matullo, G., McCarthy, M.I. (Mark), Medland, S.E. (Sarah), Merriman, A., Metspalu, A. (Andres), Meyer, B.F. (Brian F), Mohlke, K.L. (Karen L), Montgomery, G.W. (Grant), Mook-Kanamori, D. (Dennis), Munroe, P. (Patricia), North, K.E. (Kari), Nyholt, D.R. (Dale), O’connell, J.R. (Jeffery R), Ober, C. (Carole), Oldehinkel, A.J. (Albertine), Palmas, W. (Walter), Pasterkamp, G.G. (Gerard G), Patin, E. (Etienne), Pennell, C.E. (Craig), Perusse, L. (Louis), Peyser, P.A. (Patricia A.), Pirastu, M. (Mario), Polderman, T.J.C. (Tinca), Porteous, D.J. (David J.), Posthuma, D. (Danielle), Psaty, B.M. (Bruce M), Rioux, J.D. (John), Rivadeneira, F. (Fernando), Rotimi, C. (Charles), Rotter, J.I. (Jerome I.), Rudan, I. (Igor), Ruijter, H.M. (Hester ) den, Sanghera, D.K. (Dharambir K), Sattar, N. (Naveed), Schmidt, R. (Reinhold), Schulze, M.B. (Matthias), Schunkert, H. (Heribert), Scott, R.A. (Robert), Shuldiner, A.R. (Alan R), Sim, X. (Xueling), Small, N. (Neil), Smith, J.A. (Jennifer A), Sotoodehnia, N. (Nona), Tai, E.-S. (E-Shyong), Teumer, A. (Alexander), Timpson, N.J. (Nicholas), Toniolo, D. (Daniela), Tregouet, D.-A. (David-Alexandre), Tuomi, T. (Tiinamaija), Vollenweider, P. (Peter), Wang, C.A. (Carol A), Weir, D.R. (David R), Whitfield, J. (John), Wijmenga, C. (Cisca), Wong, T.-Y. (Tien-Yin), Wright, J. (John), Yang, J. (Jingyun), Yu, L. (Lei), Zemel, B.S. (Babette S.), Zonderman, A.B. (Alan B), Perola, M. (Markus), Magnusson, P.K. (Patrik), Uitterlinden, A.G. (André), Kooner, J.S. (Jaspal S.), Chasman, D.I. (Daniel), Loos, R.J.F. (Ruth), Franceschini, N. (Nora), Franke, L. (Lude), Haley, C. (Chris), Hayward, C. (Caroline), Walters, R.G. (Robin G), Perry, J.R.B. (John R. B.), Esko, T. (Tõnu), Helgason, A. (Agnar), Zwart, J-A. (John-Anker), Joshi, P.K. (Peter), Kubo, M. (Michiaki), and Wilson, J.F. (James)
Abstract: In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
Published: 2019
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7. The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia: design, results and future prospects

Author: Middeldorp, CM, Mahajan, A, Horikoshi, M, Robertson, NR, Beaumont, RN, Bradfield, JP, Bustamante, M, Cousminer, DL, Day, FR, De Silva, NM, Guxens, M, Mook-Kanamori, DO, St Pourcain, B, Warrington, NM, Adair, LS, Ahlqvist, E, Ahluwalia, TS, Almgren, P, Ang, W, Atalay, M, Auvinen, J, Bartels, M, Beckmann, JS, Bilbao, JR, Bond, T, Borja, JB, Cavadino, A, Charoen, P, Chen, Z, Coin, L, Cooper, C, Curtin, JA, Custovic, A, Das, S, Davies, GE, Dedoussis, GV, Duijts, L, Eastwood, PR, Eliasen, AU, Elliott, P, Eriksson, JG, Estivill, X, Fadista, J, Fedko, IO, Frayling, TM, Gaillard, R, Gauderman, WJ, Geller, F, Gilliland, F, Gilsanz, V, Granell, R, Grarup, N, Groop, L, Hadley, D, Hakonarson, H, Hansen, T, Hartman, CA, Hattersley, AT, Hayes, MG, Hebebrand, J, Heinrich, J, Helgeland, O, Henders, AK, Henderson, J, Henriksen, TB, Hirschhorn, JN, Hivert, M-F, Hocher, B, Holloway, JW, Holt, P, Hottenga, J-J, Hypponen, E, Iniguez, C, Johansson, S, Jugessur, A, Kahonen, M, Kalkwarf, HJ, Kaprio, J, Karhunen, V, Kemp, JP, Kerkhof, M, Koppelman, GH, Korner, A, Kotecha, S, Kreiner-Moller, E, Kulohoma, B, Kumar, A, Kutalik, Z, Lahti, J, Lappe, JM, Larsson, H, Lehtimaki, T, Lewin, AM, Li, J, Lichtenstein, P, Lindgren, CM, Lindi, V, Linneberg, A, Liu, X, Liu, J, Lowe, WL, Lundstrom, S, Lyytikainen, L-P, Ma, RCW, Mace, A, Magi, R, Magnus, P, Mamun, AA, Mannikko, M, Martin, NG, Mbarek, H, McCarthy, NS, Medland, SE, Melbye, M, Melen, E, Mohlke, KL, Monnereau, C, Morgen, CS, Morris, AP, Murray, JC, Myhre, R, Najman, JM, Nivard, MG, Nohr, EA, Nolte, IM, Ntalla, I, O'Reilly, P, Oberfield, SE, Oken, E, Oldehinkel, AJ, Pahkala, K, Palviainen, T, Panoutsopoulou, K, Pedersen, O, Pennell, CE, Pershagen, G, Pitkanen, N, Plomin, R, Power, C, Prasad, RB, Prokopenko, I, Pulkkinen, L, Raikkonen, K, Raitakari, OT, Reynolds, RM, Richmond, RC, Rivadeneira, F, Rodriguez, A, Rose, RJ, Salem, R, Santa-Marina, L, Saw, S-M, Schnurr, TM, Scott, JG, Selzam, S, Shepherd, JA, Simpson, A, Skotte, L, Sleiman, PMA, Snieder, H, Sorensen, TIA, Standl, M, Steegers, EAP, Strachan, DP, Straker, L, Strandberg, T, Taylor, M, Teo, Y-Y, Thiering, E, Torrent, M, Tyrrell, J, Uitterlinden, AG, van Beijsterveldt, T, van der Most, PJ, van Duijn, CM, Viikari, J, Vilor-Tejedor, N, Vogelezang, S, Vonk, JM, Vrijkotte, TGM, Vuoksimaa, E, Wang, CA, Watkins, WJ, Wichmann, H-E, Willemsen, G, Williams, GM, Wilson, JF, Wray, NR, Xu, S, Xu, C-J, Yaghootkar, H, Yi, L, Zafarmand, MH, Zeggini, E, Zemel, BS, Hinney, A, Lakka, TA, Whitehouse, AJO, Sunyer, J, Widen, EE, Feenstra, B, Sebert, S, Jacobsson, B, Njolstad, PR, Stoltenberg, C, Smith, GD, Lawlor, DA, Paternoster, L, Timpson, NJ, Ong, KK, Bisgaard, H, Bonnelykke, K, Jaddoe, VWV, Tiemeier, H, Jarvelin, M-R, Evans, DM, Perry, JRB, Grant, SFA, Boomsma, DI, Freathy, RM, McCarthy, MI, Felix, JF, Middeldorp, CM, Mahajan, A, Horikoshi, M, Robertson, NR, Beaumont, RN, Bradfield, JP, Bustamante, M, Cousminer, DL, Day, FR, De Silva, NM, Guxens, M, Mook-Kanamori, DO, St Pourcain, B, Warrington, NM, Adair, LS, Ahlqvist, E, Ahluwalia, TS, Almgren, P, Ang, W, Atalay, M, Auvinen, J, Bartels, M, Beckmann, JS, Bilbao, JR, Bond, T, Borja, JB, Cavadino, A, Charoen, P, Chen, Z, Coin, L, Cooper, C, Curtin, JA, Custovic, A, Das, S, Davies, GE, Dedoussis, GV, Duijts, L, Eastwood, PR, Eliasen, AU, Elliott, P, Eriksson, JG, Estivill, X, Fadista, J, Fedko, IO, Frayling, TM, Gaillard, R, Gauderman, WJ, Geller, F, Gilliland, F, Gilsanz, V, Granell, R, Grarup, N, Groop, L, Hadley, D, Hakonarson, H, Hansen, T, Hartman, CA, Hattersley, AT, Hayes, MG, Hebebrand, J, Heinrich, J, Helgeland, O, Henders, AK, Henderson, J, Henriksen, TB, Hirschhorn, JN, Hivert, M-F, Hocher, B, Holloway, JW, Holt, P, Hottenga, J-J, Hypponen, E, Iniguez, C, Johansson, S, Jugessur, A, Kahonen, M, Kalkwarf, HJ, Kaprio, J, Karhunen, V, Kemp, JP, Kerkhof, M, Koppelman, GH, Korner, A, Kotecha, S, Kreiner-Moller, E, Kulohoma, B, Kumar, A, Kutalik, Z, Lahti, J, Lappe, JM, Larsson, H, Lehtimaki, T, Lewin, AM, Li, J, Lichtenstein, P, Lindgren, CM, Lindi, V, Linneberg, A, Liu, X, Liu, J, Lowe, WL, Lundstrom, S, Lyytikainen, L-P, Ma, RCW, Mace, A, Magi, R, Magnus, P, Mamun, AA, Mannikko, M, Martin, NG, Mbarek, H, McCarthy, NS, Medland, SE, Melbye, M, Melen, E, Mohlke, KL, Monnereau, C, Morgen, CS, Morris, AP, Murray, JC, Myhre, R, Najman, JM, Nivard, MG, Nohr, EA, Nolte, IM, Ntalla, I, O'Reilly, P, Oberfield, SE, Oken, E, Oldehinkel, AJ, Pahkala, K, Palviainen, T, Panoutsopoulou, K, Pedersen, O, Pennell, CE, Pershagen, G, Pitkanen, N, Plomin, R, Power, C, Prasad, RB, Prokopenko, I, Pulkkinen, L, Raikkonen, K, Raitakari, OT, Reynolds, RM, Richmond, RC, Rivadeneira, F, Rodriguez, A, Rose, RJ, Salem, R, Santa-Marina, L, Saw, S-M, Schnurr, TM, Scott, JG, Selzam, S, Shepherd, JA, Simpson, A, Skotte, L, Sleiman, PMA, Snieder, H, Sorensen, TIA, Standl, M, Steegers, EAP, Strachan, DP, Straker, L, Strandberg, T, Taylor, M, Teo, Y-Y, Thiering, E, Torrent, M, Tyrrell, J, Uitterlinden, AG, van Beijsterveldt, T, van der Most, PJ, van Duijn, CM, Viikari, J, Vilor-Tejedor, N, Vogelezang, S, Vonk, JM, Vrijkotte, TGM, Vuoksimaa, E, Wang, CA, Watkins, WJ, Wichmann, H-E, Willemsen, G, Williams, GM, Wilson, JF, Wray, NR, Xu, S, Xu, C-J, Yaghootkar, H, Yi, L, Zafarmand, MH, Zeggini, E, Zemel, BS, Hinney, A, Lakka, TA, Whitehouse, AJO, Sunyer, J, Widen, EE, Feenstra, B, Sebert, S, Jacobsson, B, Njolstad, PR, Stoltenberg, C, Smith, GD, Lawlor, DA, Paternoster, L, Timpson, NJ, Ong, KK, Bisgaard, H, Bonnelykke, K, Jaddoe, VWV, Tiemeier, H, Jarvelin, M-R, Evans, DM, Perry, JRB, Grant, SFA, Boomsma, DI, Freathy, RM, McCarthy, MI, and Felix, JF
Abstract: The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.
Published: 2019

8. Associations of autozygosity with a broad range of human phenotypes

Author: Clark, D. W. (David W.), Okada, Y. (Yukinori), Moore, K. H. (Kristjan H. S.), Mason, D. (Dan), Pirastu, N. (Nicola), Gandin, I. (Ilaria), Mattsson, H. (Hannele), Barnes, C. L. (Catriona L. K.), Lin, K. (Kuang), Zhao, J. H. (Jing Hua), Deelen, P. (Patrick), Rohde, R. (Rebecca), Schurmann, C. (Claudia), Guo, X. (Xiuqing), Giulianini, F. (Franco), Zhang, W. (Weihua), Medina-Gomez, C. (Carolina), Karlsson, R. (Robert), Bao, Y. (Yanchun), Bartz, T. M. (Traci M.), Baumbach, C. (Clemens), Biino, G. (Ginevra), Bixley, M. J. (Matthew J.), Brumat, M. (Marco), Chai, J.-F. (Jin-Fang), Corre, T. (Tanguy), Cousminer, D. L. (Diana L.), Dekker, A. M. (Annelot M.), Eccles, D. A. (David A.), Van Eijk, K. R. (Kristel R.), Fuchsberger, C. (Christian), Gao, H. (He), Germain, M. (Marine), Gordon, S. D. (Scott D.), de Haan, H. G. (Hugoline G.), Harris, S. E. (Sarah E.), Hofer, E. (Edith), Huerta-Chagoya, A. (Alicia), Igartua, C. (Catherine), Jansen, I. E. (Iris E.), Jia, Y. (Yucheng), Kacprowski, T. (Tim), Karlsson, T. (Torgny), Kleber, M. E. (Marcus E.), Li, S. A. (Shengchao Alfred), Li-Gao, R. (Ruifang), Mahajan, A. (Anubha), Matsuda, K. (Koichi), Meidtner, K. (Karina), Meng, W. (Weihua), Montasser, M. E. (May E.), van der Most, P. J. (Peter J.), Munz, M. (Matthias), Nutile, T. (Teresa), Palviainen, T. (Teemu), Prasad, G. (Gauri), Prasad, R. B. (Rashmi B.), Priyanka, T. D. (Tallapragada Divya Sri), Rizzi, F. (Federica), Salvi, E. (Erika), Sapkota, B. R. (Bishwa R.), Shriner, D. (Daniel), Skotte, L. (Line), Smart, M. C. (Melissa C.), Smith, A. V. (Albert Vernon), van der Spek, A. (Ashley), Spracklen, C. N. (Cassandra N.), Strawbridge, R. J. (Rona J.), Tajuddin, S. M. (Salman M.), Trompet, S. (Stella), Turman, C. (Constance), Verweij, N. (Niek), Viberti, C. (Clara), Wang, L. (Lihua), Warren, H. R. (Helen R.), Wootton, R. E. (Robyn E.), Yanek, L. R. (Lisa R.), Yao, J. (Jie), Yousri, N. A. (Noha A.), Zhao, W. (Wei), Adeyemo, A. A. (Adebowale A.), Afaq, S. (Saima), Alberto Aguilar-Salinas, C. (Carlos), Akiyama, M. (Masato), Albert, M. L. (Matthew L.), Allison, M. A. (Matthew A.), Alver, M. (Maris), Aung, T. (Tin), Azizi, F. (Fereidoun), Bentley, A. R. (Amy R.), Boeing, H. (Heiner), Boerwinkle, E. (Eric), Borja, J. B. (Judith B.), de Borst, G. J. (Gert J.), Bottinger, E. P. (Erwin P.), Broer, L. (Linda), Campbell, H. (Harry), Chanock, S. (Stephen), Chee, M.-L. (Miao-Li), Chen, G. (Guanjie), Chen, Y. I. (Yii-Der I.), Chen, Z. (Zhengming), Chiu, Y.-F. (Yen-Feng), Cocca, M. (Massimiliano), Collins, F. S. (Francis S.), Concas, M. P. (Maria Pina), Corley, J. (Janie), Cugliari, G. (Giovanni), Van Dam, R. M. (Rob M.), Damulina, A. (Anna), Daneshpour, M. S. (Maryam S.), Day, F. R. (Felix R.), Delgado, G. E. (Graciela E.), Dhana, K. (Klodian), Doney, A. S. (Alexander S. F.), Doerr, M. (Marcus), Doumatey, A. P. (Ayo P.), Dzimiri, N. (Nduna), Ebenesersdottir, S. S. (S. Sunna), Elliott, J. (Joshua), Elliott, P. (Paul), Ewert, R. (Ralf), Felix, J. F. (Janine F.), Fischer, K. (Krista), Freedman, B. I. (Barry I.), Girotto, G. (Giorgia), Goel, A. (Anuj), Gogele, M. (Martin), Goodarzi, M. O. (Mark O.), Graff, M. (Mariaelisa), Granot-Hershkovitz, E. (Einat), Grodstein, F. (Francine), Guarrera, S. (Simonetta), Gudbjartsson, D. F. (Daniel F.), Guity, K. (Kamran), Gunnarsson, B. (Bjarni), Guo, Y. (Yu), Hagenaars, S. P. (Saskia P.), Haiman, C. A. (Christopher A.), Halevy, A. (Avner), Harris, T. B. (Tamara B.), Hedayati, M. (Mehdi), van Heel, D. A. (David A.), Hirata, M. (Makoto), Hofer, I. (Imo), Hsiung, C. A. (Chao Agnes), Huang, J. (Jinyan), Hung, Y.-J. (Yi-Jen), Ikram, M. A. (M. Arfan), Jagadeesan, A. (Anuradha), Jousilahti, P. (Pekka), Kamatani, Y. (Yoichiro), Kanai, M. (Masahiro), Kerrison, N. D. (Nicola D.), Kessler, T. (Thorsten), Khaw, K.-T. (Kay-Tee), Khor, C. C. (Chiea Chuen), de Kleijn, D. P. (Dominique P. V.), Koh, W.-P. (Woon-Puay), Kolcic, I. (Ivana), Kraft, P. (Peter), Kramer, B. K. (Bernhard K.), Kutalik, Z. (Zoltan), Kuusisto, J. (Johanna), Langenberg, C. (Claudia), Launer, L. J. (Lenore J.), Lawlor, D. A. (Deborah A.), Lee, I.-T. (I-Te), Lee, W.-J. (Wen-Jane), Lerch, M. M. (Markus M.), Li, L. (Liming), Liu, J. (Jianjun), Loh, M. (Marie), London, S. J. (Stephanie J.), Loomis, S. (Stephanie), Lu, Y. (Yingchang), Luan, J. (Jian'an), Magi, R. (Reedik), Manichaikul, A. W. (Ani W.), Manunta, P. (Paolo), Masson, G. (Gisli), Matoba, N. (Nana), Mei, X. W. (Xue W.), Meisinger, C. (Christa), Meitinger, T. (Thomas), Mezzavilla, M. (Massimo), Milani, L. (Lili), Millwood, I. Y. (Iona Y.), Momozawa, Y. (Yukihide), Moore, A. (Amy), Morange, P.-E. (Pierre-Emmanuel), Moreno-Macias, H. (Hortensia), Mori, T. A. (Trevor A.), Morrison, A. C. (Alanna C.), Muka, T. (Taulant), Murakami, Y. (Yoshinori), Murray, A. D. (Alison D.), de Mutsert, R. (Renee), Mychaleckyj, J. C. (Josyf C.), Nalls, M. A. (Mike A.), Nauck, M. (Matthias), Neville, M. J. (Matt J.), Nolte, I. M. (Ilja M.), Ong, K. K. (Ken K.), Orozco, L. (Lorena), Padmanabhan, S. (Sandosh), Palsson, G. (Gunnar), Pankow, J. S. (James S.), Pattaro, C. (Cristian), Pattie, A. (Alison), Polasek, O. (Ozren), Poulter, N. (Neil), Pramstaller, P. P. (Peter P.), Quintana-Murci, L. (Lluis), Raikkonen, K. (Katri), Ralhan, S. (Sarju), Rao, D. C. (Dabeeru C.), van Rheenen, W. (Wouter), Rich, S. S. (Stephen S.), Ridker, P. M. (Paul M.), Rietveld, C. A. (Cornelius A.), Robino, A. (Antonietta), van Rooij, F. J. (Frank J. A.), Ruggiero, D. (Daniela), Saba, Y. (Yasaman), Sabanayagam, C. (Charumathi), Sabater-Lleal, M. (Maria), Felicita Sala, C. (Cinzia), Salomaa, V. (Veikko), Sandow, K. (Kevin), Schmidt, H. (Helena), Scott, L. J. (Laura J.), Scott, W. R. (William R.), Sedaghati-Khayat, B. (Bahareh), Sennblad, B. (Bengt), van Setten, J. (Jessica), Sever, P. J. (Peter J.), Sheu, W. H. (Wayne H-H), Shi, Y. (Yuan), Shrestha, S. (Smeeta), Shukla, S. R. (Sharvari Rahul), Sigurdsson, J. K. (Jon K.), Sikka, T. T. (Timo Tonis), Singh, J. R. (Jai Rup), Smith, B. H. (Blair H.), Stancakova, A. (Alena), Stanton, A. (Alice), Starr, J. M. (John M.), Stefansdottir, L. (Lilja), Straker, L. (Leon), Sulem, P. (Patrick), Sveinbjornsson, G. (Gardar), Swertz, M. A. (Morris A.), Taylor, A. M. (Adele M.), Taylor, K. D. (Kent D.), Terzikhan, N. (Natalie), Tham, Y.-C. (Yih-Chung), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tillander, A. (Annika), Tracy, R. P. (Russell P.), Tusie-Luna, T. (Teresa), Tzoulaki, I. (Ioanna), Vaccargiu, S. (Simona), Vangipurapu, J. (Jagadish), Veldink, J. H. (Jan H.), Vitart, V. (Veronique), Volker, U. (Uwe), Vuoksimaa, E. (Eero), Wakil, S. M. (Salma M.), Waldenberger, M. (Melanie), Wander, G. S. (Gurpreet S.), Wang, Y. X. (Ya Xing), Wareham, N. J. (Nicholas J.), Wild, S. (Sarah), Yajnik, C. S. (Chittaranjan S.), Yuan, J.-M. (Jian-Min), Zeng, L. (Lingyao), Zhang, L. (Liang), Zhou, J. (Jie), Amin, N. (Najaf), Asselbergs, F. W. (Folkert W.), Bakker, S. J. (Stephan J. L.), Becker, D. M. (Diane M.), Lehne, B. (Benjamin), Bennett, D. A. (David A.), van den Berg, L. H. (Leonard H.), Berndt, S. I. (Sonja I.), Bharadwaj, D. (Dwaipayan), Bielak, L. F. (Lawrence F.), Bochud, M. (Murielle), Boehnke, M. (Mike), Bouchard, C. (Claude), Bradfield, J. P. (Jonathan P.), Brody, J. A. (Jennifer A.), Campbell, A. (Archie), Carmi, S. (Shai), Caulfield, M. J. (Mark J.), Cesarini, D. (David), Chambers, J. C. (John C.), Chandak, G. R. (Giriraj Ratan), Cheng, C.-Y. (Ching-Yu), Ciullo, M. (Marina), Cornelis, M. (Marilyn), Cusi, D. (Daniele), Smith, G. D. (George Davey), Deary, I. J. (Ian J.), Dorajoo, R. (Rajkumar), van Duijn, C. M. (Cornelia M.), Ellinghaus, D. (David), Erdmann, J. (Jeanette), Eriksson, J. G. (Johan G.), Evangelou, E. (Evangelos), Evans, M. K. (Michele K.), Faul, J. D. (Jessica D.), Feenstra, B. (Bjarke), Feitosa, M. (Mary), Foisy, S. (Sylvain), Franke, A. (Andre), Friedlander, Y. (Yechiel), Gasparini, P. (Paolo), Gieger, C. (Christian), Gonzalez, C. (Clicerio), Goyette, P. (Philippe), Grant, S. F. (Struan F. A.), Griffiths, L. R. (Lyn R.), Groop, L. (Leif), Gudnason, V. (Vilmundur), Gyllensten, U. (Ulf), Hakonarson, H. (Hakon), Hamsten, A. (Anders), van der Harst, P. (Pim), Heng, C.-K. (Chew-Kiat), Hicks, A. A. (Andrew A.), Hochner, H. (Hagit), Huikuri, H. (Heikki), Hunt, S. C. (Steven C.), Jaddoe, V. W. (Vincent W. V.), De Jager, P. L. (Philip L.), Johannesson, M. (Magnus), Johansson, A. (Asa), Jonas, J. B. (Jost B.), Jukema, J. W. (J. Wouter), Junttila, J. (Juhani), Kaprio, J. (Jaakko), Kardia, S. L. (Sharon L. R.), Karpe, F. (Fredrik), Kumari, M. (Meena), Laakso, M. (Markku), van der Laan, S. W. (Sander W.), Lahti, J. (Jari), Laudes, M. (Matthias), Lea, R. A. (Rodney A.), Lieb, W. (Wolfgang), Lumley, T. (Thomas), Martin, N. G. (Nicholas G.), Marz, W. (Winfried), Matullo, G. (Giuseppe), McCarthy, M. I. (Mark I.), Medland, S. E. (Sarah E.), Merriman, T. R. (Tony R.), Metspalu, A. (Andres), Meyer, B. F. (Brian F.), Mohlke, K. L. (Karen L.), Montgomery, G. W. (Grant W.), Mook-Kanamori, D. (Dennis), Munroe, P. B. (Patricia B.), North, K. E. (Kari E.), Nyholt, D. R. (Dale R.), O'connell, J. R. (Jeffery R.), Ober, C. (Carole), Oldehinkel, A. J. (Albertine J.), Palmas, W. (Walter), Palmer, C. (Colin), Pasterkamp, G. G. (Gerard G.), Patin, E. (Etienne), Pennell, C. E. (Craig E.), Perusse, L. (Louis), Peyser, P. A. (Patricia A.), Pirastu, M. (Mario), Polderman, T. J. (Tinca J. C.), Porteous, D. J. (David J.), Posthuma, D. (Danielle), Psaty, B. M. (Bruce M.), Rioux, J. D. (John D.), Rivadeneira, F. (Fernando), Rotimi, C. (Charles), Rotter, J. I. (Jerome I.), Rudan, I. (Igor), Den Ruijter, H. M. (Hester M.), Sanghera, D. K. (Dharambir K.), Sattar, N. (Naveed), Schmidt, R. (Reinhold), Schulze, M. B. (Matthias B.), Schunkert, H. (Heribert), Scott, R. A. (Robert A.), Shuldiner, A. R. (Alan R.), Sim, X. (Xueling), Small, N. (Neil), Smith, J. A. (Jennifer A.), Sotoodehnia, N. (Nona), Tai, E.-S. (E-Shyong), Teumer, A. (Alexander), Timpson, N. J. (Nicholas J.), Toniolo, D. (Daniela), Tregouet, D.-A. (David-Alexandre), Tuomi, T. (Tiinamaija), Vollenweider, P. (Peter), Wang, C. A. (Carol A.), Weir, D. R. (David R.), Whitfield, J. B. (John B.), Wijmenga, C. (Cisca), Wong, T.-Y. (Tien-Yin), Wright, J. (John), Yang, J. (Jingyun), Yu, L. (Lei), Zemel, B. S. (Babette S.), Zonderman, A. B. (Alan B.), Perola, M. (Markus), Magnusson, P. K. (Patrik K. E.), Uitterlinden, A. G. (Andre G.), Kooner, J. S. (Jaspal S.), Chasman, D. I. (Daniel I.), Loos, R. J. (Ruth J. F.), Franceschini, N. (Nora), Franke, L. (Lude), Haley, C. S. (Chris S.), Hayward, C. (Caroline), Walters, R. G. (Robin G.), Perry, J. R. (John R. B.), Esko, T. (Tonu), Helgason, A. (Agnar), Stefansson, K. (Kari), Joshi, P. K. (Peter K.), Kubo, M. (Michiaki), Wilson, J. F. (James F.), Clark, D. W. (David W.), Okada, Y. (Yukinori), Moore, K. H. (Kristjan H. S.), Mason, D. (Dan), Pirastu, N. (Nicola), Gandin, I. (Ilaria), Mattsson, H. (Hannele), Barnes, C. L. (Catriona L. K.), Lin, K. (Kuang), Zhao, J. H. (Jing Hua), Deelen, P. (Patrick), Rohde, R. (Rebecca), Schurmann, C. (Claudia), Guo, X. (Xiuqing), Giulianini, F. (Franco), Zhang, W. (Weihua), Medina-Gomez, C. (Carolina), Karlsson, R. (Robert), Bao, Y. (Yanchun), Bartz, T. M. (Traci M.), Baumbach, C. (Clemens), Biino, G. (Ginevra), Bixley, M. J. (Matthew J.), Brumat, M. (Marco), Chai, J.-F. (Jin-Fang), Corre, T. (Tanguy), Cousminer, D. L. (Diana L.), Dekker, A. M. (Annelot M.), Eccles, D. A. (David A.), Van Eijk, K. R. (Kristel R.), Fuchsberger, C. (Christian), Gao, H. (He), Germain, M. (Marine), Gordon, S. D. (Scott D.), de Haan, H. G. (Hugoline G.), Harris, S. E. (Sarah E.), Hofer, E. (Edith), Huerta-Chagoya, A. (Alicia), Igartua, C. (Catherine), Jansen, I. E. (Iris E.), Jia, Y. (Yucheng), Kacprowski, T. (Tim), Karlsson, T. (Torgny), Kleber, M. E. (Marcus E.), Li, S. A. (Shengchao Alfred), Li-Gao, R. (Ruifang), Mahajan, A. (Anubha), Matsuda, K. (Koichi), Meidtner, K. (Karina), Meng, W. (Weihua), Montasser, M. E. (May E.), van der Most, P. J. (Peter J.), Munz, M. (Matthias), Nutile, T. (Teresa), Palviainen, T. (Teemu), Prasad, G. (Gauri), Prasad, R. B. (Rashmi B.), Priyanka, T. D. (Tallapragada Divya Sri), Rizzi, F. (Federica), Salvi, E. (Erika), Sapkota, B. R. (Bishwa R.), Shriner, D. (Daniel), Skotte, L. (Line), Smart, M. C. (Melissa C.), Smith, A. V. (Albert Vernon), van der Spek, A. (Ashley), Spracklen, C. N. (Cassandra N.), Strawbridge, R. J. (Rona J.), Tajuddin, S. M. (Salman M.), Trompet, S. (Stella), Turman, C. (Constance), Verweij, N. (Niek), Viberti, C. (Clara), Wang, L. (Lihua), Warren, H. R. (Helen R.), Wootton, R. E. (Robyn E.), Yanek, L. R. (Lisa R.), Yao, J. (Jie), Yousri, N. A. (Noha A.), Zhao, W. (Wei), Adeyemo, A. A. (Adebowale A.), Afaq, S. (Saima), Alberto Aguilar-Salinas, C. (Carlos), Akiyama, M. (Masato), Albert, M. L. (Matthew L.), Allison, M. A. (Matthew A.), Alver, M. (Maris), Aung, T. (Tin), Azizi, F. (Fereidoun), Bentley, A. R. (Amy R.), Boeing, H. (Heiner), Boerwinkle, E. (Eric), Borja, J. B. (Judith B.), de Borst, G. J. (Gert J.), Bottinger, E. P. (Erwin P.), Broer, L. (Linda), Campbell, H. (Harry), Chanock, S. (Stephen), Chee, M.-L. (Miao-Li), Chen, G. (Guanjie), Chen, Y. I. (Yii-Der I.), Chen, Z. (Zhengming), Chiu, Y.-F. (Yen-Feng), Cocca, M. (Massimiliano), Collins, F. S. (Francis S.), Concas, M. P. (Maria Pina), Corley, J. (Janie), Cugliari, G. (Giovanni), Van Dam, R. M. (Rob M.), Damulina, A. (Anna), Daneshpour, M. S. (Maryam S.), Day, F. R. (Felix R.), Delgado, G. E. (Graciela E.), Dhana, K. (Klodian), Doney, A. S. (Alexander S. F.), Doerr, M. (Marcus), Doumatey, A. P. (Ayo P.), Dzimiri, N. (Nduna), Ebenesersdottir, S. S. (S. Sunna), Elliott, J. (Joshua), Elliott, P. (Paul), Ewert, R. (Ralf), Felix, J. F. (Janine F.), Fischer, K. (Krista), Freedman, B. I. (Barry I.), Girotto, G. (Giorgia), Goel, A. (Anuj), Gogele, M. (Martin), Goodarzi, M. O. (Mark O.), Graff, M. (Mariaelisa), Granot-Hershkovitz, E. (Einat), Grodstein, F. (Francine), Guarrera, S. (Simonetta), Gudbjartsson, D. F. (Daniel F.), Guity, K. (Kamran), Gunnarsson, B. (Bjarni), Guo, Y. (Yu), Hagenaars, S. P. (Saskia P.), Haiman, C. A. (Christopher A.), Halevy, A. (Avner), Harris, T. B. (Tamara B.), Hedayati, M. (Mehdi), van Heel, D. A. (David A.), Hirata, M. (Makoto), Hofer, I. (Imo), Hsiung, C. A. (Chao Agnes), Huang, J. (Jinyan), Hung, Y.-J. (Yi-Jen), Ikram, M. A. (M. Arfan), Jagadeesan, A. (Anuradha), Jousilahti, P. (Pekka), Kamatani, Y. (Yoichiro), Kanai, M. (Masahiro), Kerrison, N. D. (Nicola D.), Kessler, T. (Thorsten), Khaw, K.-T. (Kay-Tee), Khor, C. C. (Chiea Chuen), de Kleijn, D. P. (Dominique P. V.), Koh, W.-P. (Woon-Puay), Kolcic, I. (Ivana), Kraft, P. (Peter), Kramer, B. K. (Bernhard K.), Kutalik, Z. (Zoltan), Kuusisto, J. (Johanna), Langenberg, C. (Claudia), Launer, L. J. (Lenore J.), Lawlor, D. A. (Deborah A.), Lee, I.-T. (I-Te), Lee, W.-J. (Wen-Jane), Lerch, M. M. (Markus M.), Li, L. (Liming), Liu, J. (Jianjun), Loh, M. (Marie), London, S. J. (Stephanie J.), Loomis, S. (Stephanie), Lu, Y. (Yingchang), Luan, J. (Jian'an), Magi, R. (Reedik), Manichaikul, A. W. (Ani W.), Manunta, P. (Paolo), Masson, G. (Gisli), Matoba, N. (Nana), Mei, X. W. (Xue W.), Meisinger, C. (Christa), Meitinger, T. (Thomas), Mezzavilla, M. (Massimo), Milani, L. (Lili), Millwood, I. Y. (Iona Y.), Momozawa, Y. (Yukihide), Moore, A. (Amy), Morange, P.-E. (Pierre-Emmanuel), Moreno-Macias, H. (Hortensia), Mori, T. A. (Trevor A.), Morrison, A. C. (Alanna C.), Muka, T. (Taulant), Murakami, Y. (Yoshinori), Murray, A. D. (Alison D.), de Mutsert, R. (Renee), Mychaleckyj, J. C. (Josyf C.), Nalls, M. A. (Mike A.), Nauck, M. (Matthias), Neville, M. J. (Matt J.), Nolte, I. M. (Ilja M.), Ong, K. K. (Ken K.), Orozco, L. (Lorena), Padmanabhan, S. (Sandosh), Palsson, G. (Gunnar), Pankow, J. S. (James S.), Pattaro, C. (Cristian), Pattie, A. (Alison), Polasek, O. (Ozren), Poulter, N. (Neil), Pramstaller, P. P. (Peter P.), Quintana-Murci, L. (Lluis), Raikkonen, K. (Katri), Ralhan, S. (Sarju), Rao, D. C. (Dabeeru C.), van Rheenen, W. (Wouter), Rich, S. S. (Stephen S.), Ridker, P. M. (Paul M.), Rietveld, C. A. (Cornelius A.), Robino, A. (Antonietta), van Rooij, F. J. (Frank J. A.), Ruggiero, D. (Daniela), Saba, Y. (Yasaman), Sabanayagam, C. (Charumathi), Sabater-Lleal, M. (Maria), Felicita Sala, C. (Cinzia), Salomaa, V. (Veikko), Sandow, K. (Kevin), Schmidt, H. (Helena), Scott, L. J. (Laura J.), Scott, W. R. (William R.), Sedaghati-Khayat, B. (Bahareh), Sennblad, B. (Bengt), van Setten, J. (Jessica), Sever, P. J. (Peter J.), Sheu, W. H. (Wayne H-H), Shi, Y. (Yuan), Shrestha, S. (Smeeta), Shukla, S. R. (Sharvari Rahul), Sigurdsson, J. K. (Jon K.), Sikka, T. T. (Timo Tonis), Singh, J. R. (Jai Rup), Smith, B. H. (Blair H.), Stancakova, A. (Alena), Stanton, A. (Alice), Starr, J. M. (John M.), Stefansdottir, L. (Lilja), Straker, L. (Leon), Sulem, P. (Patrick), Sveinbjornsson, G. (Gardar), Swertz, M. A. (Morris A.), Taylor, A. M. (Adele M.), Taylor, K. D. (Kent D.), Terzikhan, N. (Natalie), Tham, Y.-C. (Yih-Chung), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tillander, A. (Annika), Tracy, R. P. (Russell P.), Tusie-Luna, T. (Teresa), Tzoulaki, I. (Ioanna), Vaccargiu, S. (Simona), Vangipurapu, J. (Jagadish), Veldink, J. H. (Jan H.), Vitart, V. (Veronique), Volker, U. (Uwe), Vuoksimaa, E. (Eero), Wakil, S. M. (Salma M.), Waldenberger, M. (Melanie), Wander, G. S. (Gurpreet S.), Wang, Y. X. (Ya Xing), Wareham, N. J. (Nicholas J.), Wild, S. (Sarah), Yajnik, C. S. (Chittaranjan S.), Yuan, J.-M. (Jian-Min), Zeng, L. (Lingyao), Zhang, L. (Liang), Zhou, J. (Jie), Amin, N. (Najaf), Asselbergs, F. W. (Folkert W.), Bakker, S. J. (Stephan J. L.), Becker, D. M. (Diane M.), Lehne, B. (Benjamin), Bennett, D. A. (David A.), van den Berg, L. H. (Leonard H.), Berndt, S. I. (Sonja I.), Bharadwaj, D. (Dwaipayan), Bielak, L. F. (Lawrence F.), Bochud, M. (Murielle), Boehnke, M. (Mike), Bouchard, C. (Claude), Bradfield, J. P. (Jonathan P.), Brody, J. A. (Jennifer A.), Campbell, A. (Archie), Carmi, S. (Shai), Caulfield, M. J. (Mark J.), Cesarini, D. (David), Chambers, J. C. (John C.), Chandak, G. R. (Giriraj Ratan), Cheng, C.-Y. (Ching-Yu), Ciullo, M. (Marina), Cornelis, M. (Marilyn), Cusi, D. (Daniele), Smith, G. D. (George Davey), Deary, I. J. (Ian J.), Dorajoo, R. (Rajkumar), van Duijn, C. M. (Cornelia M.), Ellinghaus, D. (David), Erdmann, J. (Jeanette), Eriksson, J. G. (Johan G.), Evangelou, E. (Evangelos), Evans, M. K. (Michele K.), Faul, J. D. (Jessica D.), Feenstra, B. (Bjarke), Feitosa, M. (Mary), Foisy, S. (Sylvain), Franke, A. (Andre), Friedlander, Y. (Yechiel), Gasparini, P. (Paolo), Gieger, C. (Christian), Gonzalez, C. (Clicerio), Goyette, P. (Philippe), Grant, S. F. (Struan F. A.), Griffiths, L. R. (Lyn R.), Groop, L. (Leif), Gudnason, V. (Vilmundur), Gyllensten, U. (Ulf), Hakonarson, H. (Hakon), Hamsten, A. (Anders), van der Harst, P. (Pim), Heng, C.-K. (Chew-Kiat), Hicks, A. A. (Andrew A.), Hochner, H. (Hagit), Huikuri, H. (Heikki), Hunt, S. C. (Steven C.), Jaddoe, V. W. (Vincent W. V.), De Jager, P. L. (Philip L.), Johannesson, M. (Magnus), Johansson, A. (Asa), Jonas, J. B. (Jost B.), Jukema, J. W. (J. Wouter), Junttila, J. (Juhani), Kaprio, J. (Jaakko), Kardia, S. L. (Sharon L. R.), Karpe, F. (Fredrik), Kumari, M. (Meena), Laakso, M. (Markku), van der Laan, S. W. (Sander W.), Lahti, J. (Jari), Laudes, M. (Matthias), Lea, R. A. (Rodney A.), Lieb, W. (Wolfgang), Lumley, T. (Thomas), Martin, N. G. (Nicholas G.), Marz, W. (Winfried), Matullo, G. (Giuseppe), McCarthy, M. I. (Mark I.), Medland, S. E. (Sarah E.), Merriman, T. R. (Tony R.), Metspalu, A. (Andres), Meyer, B. F. (Brian F.), Mohlke, K. L. (Karen L.), Montgomery, G. W. (Grant W.), Mook-Kanamori, D. (Dennis), Munroe, P. B. (Patricia B.), North, K. E. (Kari E.), Nyholt, D. R. (Dale R.), O'connell, J. R. (Jeffery R.), Ober, C. (Carole), Oldehinkel, A. J. (Albertine J.), Palmas, W. (Walter), Palmer, C. (Colin), Pasterkamp, G. G. (Gerard G.), Patin, E. (Etienne), Pennell, C. E. (Craig E.), Perusse, L. (Louis), Peyser, P. A. (Patricia A.), Pirastu, M. (Mario), Polderman, T. J. (Tinca J. C.), Porteous, D. J. (David J.), Posthuma, D. (Danielle), Psaty, B. M. (Bruce M.), Rioux, J. D. (John D.), Rivadeneira, F. (Fernando), Rotimi, C. (Charles), Rotter, J. I. (Jerome I.), Rudan, I. (Igor), Den Ruijter, H. M. (Hester M.), Sanghera, D. K. (Dharambir K.), Sattar, N. (Naveed), Schmidt, R. (Reinhold), Schulze, M. B. (Matthias B.), Schunkert, H. (Heribert), Scott, R. A. (Robert A.), Shuldiner, A. R. (Alan R.), Sim, X. (Xueling), Small, N. (Neil), Smith, J. A. (Jennifer A.), Sotoodehnia, N. (Nona), Tai, E.-S. (E-Shyong), Teumer, A. (Alexander), Timpson, N. J. (Nicholas J.), Toniolo, D. (Daniela), Tregouet, D.-A. (David-Alexandre), Tuomi, T. (Tiinamaija), Vollenweider, P. (Peter), Wang, C. A. (Carol A.), Weir, D. R. (David R.), Whitfield, J. B. (John B.), Wijmenga, C. (Cisca), Wong, T.-Y. (Tien-Yin), Wright, J. (John), Yang, J. (Jingyun), Yu, L. (Lei), Zemel, B. S. (Babette S.), Zonderman, A. B. (Alan B.), Perola, M. (Markus), Magnusson, P. K. (Patrik K. E.), Uitterlinden, A. G. (Andre G.), Kooner, J. S. (Jaspal S.), Chasman, D. I. (Daniel I.), Loos, R. J. (Ruth J. F.), Franceschini, N. (Nora), Franke, L. (Lude), Haley, C. S. (Chris S.), Hayward, C. (Caroline), Walters, R. G. (Robin G.), Perry, J. R. (John R. B.), Esko, T. (Tonu), Helgason, A. (Agnar), Stefansson, K. (Kari), Joshi, P. K. (Peter K.), Kubo, M. (Michiaki), and Wilson, J. F. (James F.)
Abstract: In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
Published: 2019

9. Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration

Author: Liu, X. (Xueping), Helenius, D. (Dorte), Skotte, L. (Line), Beaumont, R. N. (Robin N.), Wielscher, M. (Matthias), Geller, F. (Frank), Juodakis, J. (Julius), Mahajan, A. (Anubha), Bradfield, J. P. (Jonathan P.), Lin, F. T. (Frederick Tj), Vogelezang, S. (Suzanne), Bustamante, M. (Mariona), Ahluwalia, T. S. (Tarunveer S.), Pitkanen, N. (Niina), Wang, C. A. (Carol A.), Bacelis, J. (Jonas), Borges, M. C. (Maria C.), Zhang, G. (Ge), Bedell, B. A. (Bruce A.), Rossi, R. M. (Robert M.), Skogstrand, K. (Kristin), Peng, S. (Shouneng), Thompson, W. K. (Wesley K.), Appadurai, V. (Vivek), Lawlor, D. A. (Debbie A.), Kalliala, I. (Ilkka), Power, C. (Christine), McCarthy, M. I. (Mark, I), Boyd, H. A. (Heather A.), Marazita, M. L. (Mary L.), Hakonarson, H. (Hakon), Hayes, M. G. (M. Geoffrey), Scholtens, D. M. (Denise M.), Rivadeneira, F. (Fernando), Jaddoe, V. W. (Vincent W. V.), Vinding, R. K. (Rebecca K.), Bisgaard, H. (Hans), Knight, B. A. (Bridget A.), Pahkala, K. (Katja), Raitakari, O. (Olli), Helgeland, O. (Oyvind), Johansson, S. (Stefan), Njolstad, P. R. (Pal R.), Fadista, J. (Joao), Schork, A. J. (Andrew J.), Nudel, R. (Ron), Miller, D. E. (Daniel E.), Chen, X. (Xiaoting), Weirauch, M. T. (Matthew T.), Mortensen, P. B. (Preben Bo), Borglum, A. D. (Anders D.), Nordentoft, M. (Merete), Mors, O. (Ole), Hao, K. (Ke), Ryckman, K. K. (Kelli K.), Hougaard, D. M. (David M.), Kottyan, L. C. (Leah C.), Pennell, C. E. (Craig E.), Lyytikainen, L.-P. (Leo-Pekka), Bonnelykke, K. (Klaus), Vrijheid, M. (Martine), Felix, J. F. (Janine F.), Lowe, W. L. (William L., Jr.), Grant, S. F. (Struan Fa), Hypponen, E. (Elina), Jacobsson, B. (Bo), Järvelin, M.-R. (Marjo-Riitta), Muglia, L. J. (Louis J.), Murray, J. C. (Jeffrey C.), Freathy, R. M. (Rachel M.), Werge, T. M. (Thomas M.), Melbye, M. (Mads), Buil, A. (Alfonso), Feenstra, B. (Bjarke), Liu, X. (Xueping), Helenius, D. (Dorte), Skotte, L. (Line), Beaumont, R. N. (Robin N.), Wielscher, M. (Matthias), Geller, F. (Frank), Juodakis, J. (Julius), Mahajan, A. (Anubha), Bradfield, J. P. (Jonathan P.), Lin, F. T. (Frederick Tj), Vogelezang, S. (Suzanne), Bustamante, M. (Mariona), Ahluwalia, T. S. (Tarunveer S.), Pitkanen, N. (Niina), Wang, C. A. (Carol A.), Bacelis, J. (Jonas), Borges, M. C. (Maria C.), Zhang, G. (Ge), Bedell, B. A. (Bruce A.), Rossi, R. M. (Robert M.), Skogstrand, K. (Kristin), Peng, S. (Shouneng), Thompson, W. K. (Wesley K.), Appadurai, V. (Vivek), Lawlor, D. A. (Debbie A.), Kalliala, I. (Ilkka), Power, C. (Christine), McCarthy, M. I. (Mark, I), Boyd, H. A. (Heather A.), Marazita, M. L. (Mary L.), Hakonarson, H. (Hakon), Hayes, M. G. (M. Geoffrey), Scholtens, D. M. (Denise M.), Rivadeneira, F. (Fernando), Jaddoe, V. W. (Vincent W. V.), Vinding, R. K. (Rebecca K.), Bisgaard, H. (Hans), Knight, B. A. (Bridget A.), Pahkala, K. (Katja), Raitakari, O. (Olli), Helgeland, O. (Oyvind), Johansson, S. (Stefan), Njolstad, P. R. (Pal R.), Fadista, J. (Joao), Schork, A. J. (Andrew J.), Nudel, R. (Ron), Miller, D. E. (Daniel E.), Chen, X. (Xiaoting), Weirauch, M. T. (Matthew T.), Mortensen, P. B. (Preben Bo), Borglum, A. D. (Anders D.), Nordentoft, M. (Merete), Mors, O. (Ole), Hao, K. (Ke), Ryckman, K. K. (Kelli K.), Hougaard, D. M. (David M.), Kottyan, L. C. (Leah C.), Pennell, C. E. (Craig E.), Lyytikainen, L.-P. (Leo-Pekka), Bonnelykke, K. (Klaus), Vrijheid, M. (Martine), Felix, J. F. (Janine F.), Lowe, W. L. (William L., Jr.), Grant, S. F. (Struan Fa), Hypponen, E. (Elina), Jacobsson, B. (Bo), Järvelin, M.-R. (Marjo-Riitta), Muglia, L. J. (Louis J.), Murray, J. C. (Jeffrey C.), Freathy, R. M. (Rachel M.), Werge, T. M. (Thomas M.), Melbye, M. (Mads), Buil, A. (Alfonso), and Feenstra, B. (Bjarke)
Abstract: The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10−14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.
Published: 2019

10. Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration

Author: Liu, XP, Helenius, D, Skotte, L, Beaumont, RN, Vogelezang, Suzanne, Rivadeneira, Fernando, Jaddoe, Vincent, Felix, Janine, Wielscher, M, Geller, F, Liu, XP, Helenius, D, Skotte, L, Beaumont, RN, Vogelezang, Suzanne, Rivadeneira, Fernando, Jaddoe, Vincent, Felix, Janine, Wielscher, M, and Geller, F
Published: 2019

11. Associations of autozygosity with a broad range of human phenotypes

Author: Clark, D.W., Okada, Y., Moore, K.H.S., Mason, D., Pirastu, N., Gandin, I., Mattsson, H., Barnes, C.L.K., Lin, K., Zhao, J.H., Deelen, P., Rohde, R., Schurmann, C., Guo, X., Giulianini, F., Zhang, W., Medina-Gomez, C., Karlsson, R., Bao, Y., Bartz, T.M., Baumbach, C., Biino, G., Bixley, M.J., Brumat, M., Chai, J.F., Corre, T., Cousminer, D.L., Dekker, A.M., Eccles, D.A., van Eijk, K.R., Fuchsberger, C., Gao, H., Germain, M., Gordon, S.D., de Haan, H.G., Harris, S.E., Hofer, E., Huerta-Chagoya, A., Igartua, C., Jansen, I.E., Jia, Y., Kacprowski, T., Karlsson, T., Kleber, M.E., Li, S.A., Li-Gao, R., Mahajan, A., Matsuda, K., Meidtner, K., Meng, W., Montasser, M.E., van der Most, P.J., Munz, M., Nutile, T., Palviainen, T., Prasad, G., Prasad, R.B., Priyanka, T.D.S., Rizzi, F., Salvi, E., Sapkota, B.R., Shriner, D., Skotte, L., Smart, M.C., Smith, A.V., van der Spek, A., Spracklen, C.N., Strawbridge, R.J., Tajuddin, S.M., Trompet, S., Turman, C., Verweij, N., Viberti, C., Wang, L., Warren, H.R., Wootton, R.E., Yanek, L.R., Yao, J., Yousri, N.A., Zhao, W., Adeyemo, A.A., Afaq, S., Aguilar-Salinas, C.A., Akiyama, M., Albert, M.L., Allison, M.A., Alver, M., Aung, T., Azizi, F., Bentley, A.R., Boeing, H., Boerwinkle, E., Borja, J.B., de Borst, G.J., Bottinger, E.P., Broer, L., Campbell, H., Chanock, S., Chee, M.L., Chen, G., Clark, D.W., Okada, Y., Moore, K.H.S., Mason, D., Pirastu, N., Gandin, I., Mattsson, H., Barnes, C.L.K., Lin, K., Zhao, J.H., Deelen, P., Rohde, R., Schurmann, C., Guo, X., Giulianini, F., Zhang, W., Medina-Gomez, C., Karlsson, R., Bao, Y., Bartz, T.M., Baumbach, C., Biino, G., Bixley, M.J., Brumat, M., Chai, J.F., Corre, T., Cousminer, D.L., Dekker, A.M., Eccles, D.A., van Eijk, K.R., Fuchsberger, C., Gao, H., Germain, M., Gordon, S.D., de Haan, H.G., Harris, S.E., Hofer, E., Huerta-Chagoya, A., Igartua, C., Jansen, I.E., Jia, Y., Kacprowski, T., Karlsson, T., Kleber, M.E., Li, S.A., Li-Gao, R., Mahajan, A., Matsuda, K., Meidtner, K., Meng, W., Montasser, M.E., van der Most, P.J., Munz, M., Nutile, T., Palviainen, T., Prasad, G., Prasad, R.B., Priyanka, T.D.S., Rizzi, F., Salvi, E., Sapkota, B.R., Shriner, D., Skotte, L., Smart, M.C., Smith, A.V., van der Spek, A., Spracklen, C.N., Strawbridge, R.J., Tajuddin, S.M., Trompet, S., Turman, C., Verweij, N., Viberti, C., Wang, L., Warren, H.R., Wootton, R.E., Yanek, L.R., Yao, J., Yousri, N.A., Zhao, W., Adeyemo, A.A., Afaq, S., Aguilar-Salinas, C.A., Akiyama, M., Albert, M.L., Allison, M.A., Alver, M., Aung, T., Azizi, F., Bentley, A.R., Boeing, H., Boerwinkle, E., Borja, J.B., de Borst, G.J., Bottinger, E.P., Broer, L., Campbell, H., Chanock, S., Chee, M.L., and Chen, G.
Abstract: In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
Published: 2019

12. Maternal and fetal genetic contribution to gestational weight gain

Author: Warrington, N.M. (N. M.), Richmond, R.C. (Rebecca C.), Fenstra, B. (B.), Myhre, R. (Ronny), Gaillard, R. (Romy), Paternoster, L. (L.), Wang, C.A. (C. A.), Beaumont, R.N. (R. N.), Das, S. (Shikta), Murcia, M. (Mario), Barton, S.J. (Sheila), Espinosa, A. (A.), Thiering, E. (Elisabeth), Atalay, M. (Mustafa), Pitkanen, N. (Niina), Ntalla, I. (Ioanna), Jonsson, A.E. (A. E.), Freathy, R.M. (Rachel), Karhunen, V. (V.), Tiesler, C.M.T. (C. M.T.), Allard, C. (Catherine), Crawford, A. (A.), Ring, S.M. (Susan), Melbye, M. (Mads), Magnus, P. (Per), Rivadeneira, F. (F.), Skotte, L. (L.), Hansen, T. (Torben), Marsh, J.A. (Julie), Guxens Junyent, M. (Mònica), Holloway, J.W. (J. W.), Grallert, H. (Harald), Jaddoe, V.W.V. (Vincent), Lowe, W.L. (W. L.), Roumeliotaki, T. (Theano), Hattersley, A.T. (Andrew), Lindi, V. (Virpi), Pahkala, K. (Katja), Panoutsopoulou, K. (K.), Standl, M. (M.), Flexeder, C. (Claudia), Bouchard, L. (Luigi), Aagaard Nohr, E. (E.), Santa-Marina, L. (Loreto), Kogevinas, M. (Manolis), Niinikoski, H. (H.), Dedoussis, G.V. (George), Heinrich, J. (J.), Reynolds, R.M. (Rebecca), Lakka, T.A. (Timo), Zeggini, E. (Eleftheria), Raitakari, O.T. (O. T.), Chatzi, L. (Leda), Inskip, H.M. (Hazel), Bustamante, M. (Mariona), Hivert, M.-F. (Marie-France), Jarvelin, M.-R. (M. R.), Sørensen, T.I.A. (Thorkild), Pennell, C.E. (Craig), Felix, J.F. (J. F.), Jacobsson, B. (B.), Geller, F. (Frank), Evans, D.M. (D. M.), Lawlor, D.A. (D. A.), Warrington, N.M. (N. M.), Richmond, R.C. (Rebecca C.), Fenstra, B. (B.), Myhre, R. (Ronny), Gaillard, R. (Romy), Paternoster, L. (L.), Wang, C.A. (C. A.), Beaumont, R.N. (R. N.), Das, S. (Shikta), Murcia, M. (Mario), Barton, S.J. (Sheila), Espinosa, A. (A.), Thiering, E. (Elisabeth), Atalay, M. (Mustafa), Pitkanen, N. (Niina), Ntalla, I. (Ioanna), Jonsson, A.E. (A. E.), Freathy, R.M. (Rachel), Karhunen, V. (V.), Tiesler, C.M.T. (C. M.T.), Allard, C. (Catherine), Crawford, A. (A.), Ring, S.M. (Susan), Melbye, M. (Mads), Magnus, P. (Per), Rivadeneira, F. (F.), Skotte, L. (L.), Hansen, T. (Torben), Marsh, J.A. (Julie), Guxens Junyent, M. (Mònica), Holloway, J.W. (J. W.), Grallert, H. (Harald), Jaddoe, V.W.V. (Vincent), Lowe, W.L. (W. L.), Roumeliotaki, T. (Theano), Hattersley, A.T. (Andrew), Lindi, V. (Virpi), Pahkala, K. (Katja), Panoutsopoulou, K. (K.), Standl, M. (M.), Flexeder, C. (Claudia), Bouchard, L. (Luigi), Aagaard Nohr, E. (E.), Santa-Marina, L. (Loreto), Kogevinas, M. (Manolis), Niinikoski, H. (H.), Dedoussis, G.V. (George), Heinrich, J. (J.), Reynolds, R.M. (Rebecca), Lakka, T.A. (Timo), Zeggini, E. (Eleftheria), Raitakari, O.T. (O. T.), Chatzi, L. (Leda), Inskip, H.M. (Hazel), Bustamante, M. (Mariona), Hivert, M.-F. (Marie-France), Jarvelin, M.-R. (M. R.), Sørensen, T.I.A. (Thorkild), Pennell, C.E. (Craig), Felix, J.F. (J. F.), Jacobsson, B. (B.), Geller, F. (Frank), Evans, D.M. (D. M.), and Lawlor, D.A. (D. A.)
Abstract: Background:Clinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG.Participants and methods:A genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10 543 mothers and 16 317 offspring of European origin, with replication in 10 660 mothers and 7561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (for example, maternal body mass index (BMI) and glucose, birth weight).Results:Approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and the fetal genome made a surprisingly minor contribution to explain variation in GWG. Variants near the pregnancy-specific beta-1 glycoprotein 5 (PSG5) gene reached genome-wide significance (P=1.71 × 10 â '8) for total GWG in the offspring genome, but did not replicate. Some established variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birth weight variants were largely unrelated to GWG.Conclusions:We found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outc
Published: 2018
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13. Maternal and fetal genetic contribution to gestational weight gain

Author: Warrington, N. M. (N. M.), Richmond, R. (R.), Fenstra, B. (B.), Myhre, R. (R.), Gaillard, R. (R.), Paternoster, L. (L.), Wang, C. A. (C. A.), Beaumont, R. N. (R. N.), Das, S. (S.), Murcia, M. (M.), Barton, S. J. (S. J.), Espinosa, A. (A.), Thiering, E. (E.), Atalay, M. (M.), Pitkanen, N. (N.), Ntalla, I. (I.), Jonsson, A. E. (A. E.), Freathy, R. (R.), Karhunen, V. (V.), Tiesler, C. M. (C. M. T.), Allard, C. (C.), Crawford, A. (A.), Ring, S. M. (S. M.), Melbye, M. (M.), Magnus, P. (P.), Rivadeneira, F. (F.), Skotte, L. (L.), Hansen, T. (T.), Marsh, J. (J.), Guxens, M. (M.), Holloway, J. W. (J. W.), Grallert, H. (H.), Jaddoe, V. W. (V. W. V.), Lowe, W. L. (W. L.), Roumeliotaki, T. (T.), Hattersley, A. T. (A. T.), Lindi, V. (V.), Pahkala, K. (K.), Panoutsopoulou, K. (K.), Standl, M. (M.), Flexeder, C. (C.), Bouchard, L. (L.), Aagaard Nohr, E. (E.), Santa Marina, L. (L.), Kogevinas, M. (M.), Niinikoski, H. (H.), Dedoussis, G. (G.), Heinrich, J. (J.), Reynolds, R. M. (R. M.), Lakka, T. (T.), Zeggini, E. (E.), Raitakari, O. T. (O. T.), Chatzi, L. (L.), Inskip, H. M. (H. M.), Bustamante, M. (M.), Hivert, M.-F. (M-F), Järvelin, M.-R. (M-R), Sorensen, T. I. (T. I. A.), Pennell, C. (C.), Felix, J. F. (J. F.), Jacobsson, B. (B.), Geller, F. (F.), Evans, D. M. (D. M.), Lawlor, D. A. (D. A.), Warrington, N. M. (N. M.), Richmond, R. (R.), Fenstra, B. (B.), Myhre, R. (R.), Gaillard, R. (R.), Paternoster, L. (L.), Wang, C. A. (C. A.), Beaumont, R. N. (R. N.), Das, S. (S.), Murcia, M. (M.), Barton, S. J. (S. J.), Espinosa, A. (A.), Thiering, E. (E.), Atalay, M. (M.), Pitkanen, N. (N.), Ntalla, I. (I.), Jonsson, A. E. (A. E.), Freathy, R. (R.), Karhunen, V. (V.), Tiesler, C. M. (C. M. T.), Allard, C. (C.), Crawford, A. (A.), Ring, S. M. (S. M.), Melbye, M. (M.), Magnus, P. (P.), Rivadeneira, F. (F.), Skotte, L. (L.), Hansen, T. (T.), Marsh, J. (J.), Guxens, M. (M.), Holloway, J. W. (J. W.), Grallert, H. (H.), Jaddoe, V. W. (V. W. V.), Lowe, W. L. (W. L.), Roumeliotaki, T. (T.), Hattersley, A. T. (A. T.), Lindi, V. (V.), Pahkala, K. (K.), Panoutsopoulou, K. (K.), Standl, M. (M.), Flexeder, C. (C.), Bouchard, L. (L.), Aagaard Nohr, E. (E.), Santa Marina, L. (L.), Kogevinas, M. (M.), Niinikoski, H. (H.), Dedoussis, G. (G.), Heinrich, J. (J.), Reynolds, R. M. (R. M.), Lakka, T. (T.), Zeggini, E. (E.), Raitakari, O. T. (O. T.), Chatzi, L. (L.), Inskip, H. M. (H. M.), Bustamante, M. (M.), Hivert, M.-F. (M-F), Järvelin, M.-R. (M-R), Sorensen, T. I. (T. I. A.), Pennell, C. (C.), Felix, J. F. (J. F.), Jacobsson, B. (B.), Geller, F. (F.), Evans, D. M. (D. M.), and Lawlor, D. A. (D. A.)
Abstract: Background: Clinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG. Participants and methods: A genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10 543 mothers and 16 317 offspring of European origin, with replication in 10 660 mothers and 7561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (for example, maternal body mass index (BMI) and glucose, birth weight). Results: Approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and the fetal genome made a surprisingly minor contribution to explain variation in GWG. Variants near the pregnancy-specific beta-1 glycoprotein 5 (PSG5) gene reached genome-wide significance (P=1.71 × 10−8) for total GWG in the offspring genome, but did not replicate. Some established variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birth weight variants were largely unrelated to GWG. Conclusions: We found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring
Published: 2018

14. Maternal and fetal genetic contribution to gestational weight gain

Author: Warrington, N M, Richmond, R, Fenstra, B, Myhre, R, Gaillard, R, Paternoster, L, Wang, C A, Beaumont, R N, Das, S, Murcia, M, Barton, S J, Espinosa, A, Thiering, E, Atalay, M, Pitkänen, N, Ntalla, I, Jonsson, A E, Freathy, R, Karhunen, V, Tiesler, C M T, Allard, C, Crawford, A, Ring, S M, Melbye, M, Magnus, P, Rivadeneira, F, Skotte, L, Hansen, T, Marsh, J, Guxens, M, Holloway, J W, Grallert, H, Jaddoe, V W V, Lowe, W L, Roumeliotaki, T, Hattersley, A T, Lindi, V, Pahkala, K, Panoutsopoulou, K, Standl, M, Flexeder, C, Bouchard, L, Aagaard Nohr, E, Marina, L Santa, Kogevinas, M, Niinikoski, H, Dedoussis, G, Heinrich, J, Reynolds, R M, Lakka, T, Zeggini, E, Raitakari, O T, Chatzi, L, Inskip, H M, Bustamante, M, Hivert, M-F, Jarvelin, M-R, Sørensen, T I A, Pennell, C, Felix, J F, Jacobsson, B, Geller, F, Evans, D M, Lawlor, D A, Warrington, N M, Richmond, R, Fenstra, B, Myhre, R, Gaillard, R, Paternoster, L, Wang, C A, Beaumont, R N, Das, S, Murcia, M, Barton, S J, Espinosa, A, Thiering, E, Atalay, M, Pitkänen, N, Ntalla, I, Jonsson, A E, Freathy, R, Karhunen, V, Tiesler, C M T, Allard, C, Crawford, A, Ring, S M, Melbye, M, Magnus, P, Rivadeneira, F, Skotte, L, Hansen, T, Marsh, J, Guxens, M, Holloway, J W, Grallert, H, Jaddoe, V W V, Lowe, W L, Roumeliotaki, T, Hattersley, A T, Lindi, V, Pahkala, K, Panoutsopoulou, K, Standl, M, Flexeder, C, Bouchard, L, Aagaard Nohr, E, Marina, L Santa, Kogevinas, M, Niinikoski, H, Dedoussis, G, Heinrich, J, Reynolds, R M, Lakka, T, Zeggini, E, Raitakari, O T, Chatzi, L, Inskip, H M, Bustamante, M, Hivert, M-F, Jarvelin, M-R, Sørensen, T I A, Pennell, C, Felix, J F, Jacobsson, B, Geller, F, Evans, D M, and Lawlor, D A
Abstract: BACKGROUND: Clinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG.PARTICIPANTS AND METHODS: A genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10 543 mothers and 16 317 offspring of European origin, with replication in 10 660 mothers and 7561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (for example, maternal body mass index (BMI) and glucose, birth weight).RESULTS: Approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and the fetal genome made a surprisingly minor contribution to explain variation in GWG. Variants near the pregnancy-specific beta-1 glycoprotein 5 (PSG5) gene reached genome-wide significance (P=1.71 × 10-8) for total GWG in the offspring genome, but did not replicate. Some established variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birth weight variants were largely unrelated to GWG.CONCLUSIONS: We found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and late
Published: 2018

15. Maternal and fetal genetic contribution to gestational weight gain

Author: Warrington, NM, Richmond, R, Fenstra, B, Myhre, R, Gaillard, Romy, Paternoster, L, Wang, CA, Beaumont, RN, Das, S, Murcia, M, Barton, SJ, Espinosa, A, Thiering, E, Atalay, M, Pitkanen, N, Ntalla, I, Jonsson, AE, Freathy, R, Karhunen, V, Tiesler, CMT, Allard, C, Crawford, A, Ring, SM, Melbye, M, Magnus, P, Rivadeneira, Fernando, Skotte, L, Hansen, T, Marsh, J, Guxens Junyent, Monica, Holloway, JW, Grallert, H, Jaddoe, Vincent, Lowe, WL, Roumeliotaki, T, Hattersley, AT, Lindi, V, Pahkala, K, Panoutsopoulou, K, Standl, M, Flexeder, C, Bouchard, L, Nohr, E, Marina, L, Kogevinas, M, Niinikoski, H, Dedoussis, G, Heinrich, J, Reynolds, RM, Lakka, T, Zeggini, E, Raitakari, OT, Chatzi, L, Inskip, HM, Bustamante, M, Hivert, MF, Jarvelin, MR, Sorensen, TIA, Pennell, C, Felix, Janine, Jacobsson, B, Geller, F, Evans, DM, Lawlor, DA, Warrington, NM, Richmond, R, Fenstra, B, Myhre, R, Gaillard, Romy, Paternoster, L, Wang, CA, Beaumont, RN, Das, S, Murcia, M, Barton, SJ, Espinosa, A, Thiering, E, Atalay, M, Pitkanen, N, Ntalla, I, Jonsson, AE, Freathy, R, Karhunen, V, Tiesler, CMT, Allard, C, Crawford, A, Ring, SM, Melbye, M, Magnus, P, Rivadeneira, Fernando, Skotte, L, Hansen, T, Marsh, J, Guxens Junyent, Monica, Holloway, JW, Grallert, H, Jaddoe, Vincent, Lowe, WL, Roumeliotaki, T, Hattersley, AT, Lindi, V, Pahkala, K, Panoutsopoulou, K, Standl, M, Flexeder, C, Bouchard, L, Nohr, E, Marina, L, Kogevinas, M, Niinikoski, H, Dedoussis, G, Heinrich, J, Reynolds, RM, Lakka, T, Zeggini, E, Raitakari, OT, Chatzi, L, Inskip, HM, Bustamante, M, Hivert, MF, Jarvelin, MR, Sorensen, TIA, Pennell, C, Felix, Janine, Jacobsson, B, Geller, F, Evans, DM, and Lawlor, DA
Published: 2018

16. Erratum: The role of miRNAs in human papilloma virus (HPV)-associated cancers: bridging between HPV-related head and neck cancer and cervical cancer

Author: Lajer, C B, primary, Garnæs, E, additional, Friis-Hansen, L, additional, Norrild, B, additional, Therkildsen, M H, additional, Glud, M, additional, Rossing, M, additional, Lajer, H, additional, Svane, D, additional, Skotte, L, additional, Specht, L, additional, Buchwald, C, additional, and Nielsen, F C, additional
Published: 2017
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17. An Aboriginal Australian Genome Reveals Separate Human Dispersals into Asia

Author: Xiao, Xiaosen, Wang, Yong, Lohmueller, Kirk, Rasmussen, Rasmus, Albrechtsen, Anders, Li, Line, Li, Stinus, Metspalu, Mait, Jombart, Thibaut, Kivisild, Toomas, Zhai, Weiwei, Eriksson, Anders, Manica, Andrea, Orlando, Ludovic, De La Vega, Francisco, Tridico, Silvana, Metspalu, Ene, Nielsen, Kasper, Ávila-Arcos, María, Moreno-Mayar, J. Víctor, Muller, Craig, Dortch, Joe, Gilbert, Thomas, Lund, Ole, Wesolowska, Agata, Karmin, Monika, Weinert, Lucy, Wang, B., Li, Jun, Tai, Shuaishuai, Xiao, Fei, Hanihara, Tsunehiko, Van Driem, George, Jha, Aashish, Ricaut, François-Xavier, De Knijff, Peter, Migliano, Andrea, Gallego Romero, Irene, Kristiansen, Karsten, Lambert, David, Brunak, Søren, Forster, Peter, Brinkmann, Bernd, Nehlich, Olaf, Bunce, Michael, Richards, Richard, Gupta, Ramneek, Bustamante, Carlos, Krogh, Anders, Foley, Robert, Lahr, Marta, Balloux, François, Villems, Richard, Nielsen, Rasmus, Wang, Jun, Willerslev, Eske, Rasmussen, M., Guo, X., Rasmussen, S., Skotte, L., Lindgreen, S., De La Vega, M., Avila-Arcos, M., Gilbert, M., Weinert, A., Ricaut, X., Lambert, M., Richards, M., Foley, A., Sicheritz-Ponten, Thomas, PLA University of Science and Technology, Department of Biological Statistics and Computational Biology, Cornell University, Section of Biostatistics [Copenhagen], Department of Public Health [Copenhagen], Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), University of Tartu, Medical Research Council, Centre for Outbreak Analysis and Modelling (MRC), Imperial College Faculty of Medicine, Leverhulme Centre for Human Evolutionary Studies University of Cambridge, University of Cambridge [UK] (CAM), Swedish Institute of Space Physics [Uppsala] (IRF), Section for GeoGenetics, Globe Institute, Center for Biological Sequence Analysis, Technical University of Denmark [Lyngby] (DTU), Department of Veterinary Medicine, University of Cambridge, Cambridge, UK, Centre d'économie industrielle i3 (CERNA i3), Centre National de la Recherche Scientifique (CNRS)-PSL Research University (PSL)-MINES ParisTech - École nationale supérieure des mines de Paris, Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Department of Biochemistry and Molecular Biology, University of Southern Denmark (SDU), University of Edinburgh, UMR 6578 : Adaptabilité Biologique et Culturelle (UAABC), Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2, Dept Integrat Biol, Chinese Academy of Agricultural Mechanization Sciences (CCCME), Laboratoire sols, solides, structures - risques [Grenoble] (3SR), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Service de Médecine interne A et polyclinique médicale [CHU Limoges], CHU Limoges, Department of Pathology [Stanford], Stanford Medicine, Stanford University-Stanford University, Medical Research Council Centre for Outbreak Analysis and Modelling, Imperial College London-Faculty of Medicine-Department of Infectious Disease Epidemiology, State Key Laboratory for Mineral Deposits Research, Nanjing University (NJU), Department of Human Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Interactions Virus-Hôte et Maladies Hépatiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Virologie, Anthropologie Moléculaire et Imagerie de Synthèse (AMIS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Department of Biology [Copenhagen], Faculty of Science [Copenhagen], Center for Biological Sequence Analysis [Lyngby], Department of Physics, University of Sussex, UMR 6578 : Anthropologie Bio-Culturelle (UAABC), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), State Key Laboratory of Lithospheric Evolution (SKL), Institute of Geology and Geophysics [Beijing] (IGG), Chinese Academy of Sciences [Beijing] (CAS)-Chinese Academy of Sciences [Beijing] (CAS), Stanford University [Stanford], Nanjing University of Science and Technology (NJUST), Cornell University [New York], Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Universiteit Leiden-Universiteit Leiden, Danmarks Tekniske Universitet = Technical University of Denmark (DTU), and Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0106 biological sciences, Male, MESH: Sequence Analysis, DNA, Native Hawaiian or Other Pacific Islander, MESH: Emigration and Immigration, [SHS.ANTHRO-BIO]Humanities and Social Sciences/Biological anthropology, Ethnic group, 01 natural sciences, Linkage Disequilibrium, Gene flow, Gene Frequency, MESH: Hominidae, Ethnicity, MESH: Animals, MESH: Phylogeny, Phylogeny, Genetics, 0303 health sciences, education.field_of_study, Multidisciplinary, MESH: Asian Continental Ancestry Group, biology, Asia, Eastern, MESH: Asia, MESH: Polymorphism, Single Nucleotide, New guinea, Hominidae, MESH: European Continental Ancestry Group, Emigration and Immigration, Human evolution, MESH: Linkage Disequilibrium, Ethnology, MESH: Ethnic Groups, MESH: Genome, Mitochondrial, MESH: Oceanic Ancestry Group, Gene Flow, Asia, Population, Black People, MESH: Genetics, Population, 010603 evolutionary biology, DNA, Mitochondrial, Polymorphism, Single Nucleotide, White People, Article, 03 medical and health sciences, Asian People, MESH: Computer Simulation, MESH: Gene Frequency, MESH: Western Australia, Animals, Humans, East Asia, Computer Simulation, education, MESH: Gene Flow, MESH: Genome, Human, 030304 developmental biology, MESH: Humans, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Genome, Human, MESH: DNA, Mitochondrial, Sequence Analysis, DNA, Western Australia, MESH: Haplotypes, biology.organism_classification, MESH: Far East, MESH: Male, Genetics, Population, Haplotypes, Genome, Mitochondrial, Biological dispersal, MESH: African Continental Ancestry Group
Abstract: International audience; We present an Aboriginal Australian genomic sequence obtained from a 100-year-old lock of hair donated by an Aboriginal man from southern Western Australia in the early 20th century. We detect no evidence of European admixture and estimate contamination levels to be below 0.5%. We show that Aboriginal Australians are descendants of an early human dispersal into eastern Asia, possibly 62,000 to 75,000 years ago. This dispersal is separate from the one that gave rise to modern Asians 25,000 to 38,000 years ago. We also find evidence of gene flow between populations of the two dispersal waves prior to the divergence of Native Americans from modern Asian ancestors. Our findings support the hypothesis that present-day Aboriginal Australians descend from the earliest humans to occupy Australia, likely representing one of the oldest continuous populations outside Africa.
Published: 2011
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18. Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes

Author: Albrechtsen, A., Grarup, N., Li, Y., Sparso, T., Tian, G., Cao, H., Jiang, T., Kim, S. Y., Korneliussen, T., Li, Q., Nie, C., Wu, R., Skotte, L., Morris, A. P., Ladenvall, C., Cauchi, S., Stancakova, A., Andersen, G., Astrup, A., Banasik, K., Bennett, A. J., Bolund, L., Charpentier, G., Chen, Y., Dekker, J. M., Doney, A. S. F., Dorkhan, M., Forsen, T., Frayling, T. M., Groves, C. J., Gui, Y., Hallmans, Göran, Hattersley, A. T., He, K., Hitman, G. A., Holmkvist, J., Huang, S., Jiang, H., Jin, X., Justesen, J. M., Kristiansen, K., Kuusisto, J., Lajer, M., Lantieri, O., Li, W., Liang, H., Liao, Q., Liu, X., Ma, T., Ma, X., Manijak, M. P., Marre, M., Mokrosinski, J., Morris, A. D., Mu, B., Nielsen, A. A., Nijpels, G., Nilsson, P., Palmer, C. N. A., Rayner, N. W., Renstrom, F., Ribel-Madsen, R., Robertson, N., Rolandsson, Olov, Rossing, P., Schwartz, T. W., Slagboom, P. E., Sterner, M., Tang, M., Tarnow, L., Tuomi, T., van't Riet, E., van Leeuwen, N., Varga, T. V., Vestmar, M. A., Walker, M., Wang, B., Wang, Y., Wu, H., Xi, F., Yengo, L., Yu, C., Zhang, X., Zhang, J., Zhang, Q., Zhang, W., Zheng, H., Zhou, Y., Altshuler, D., 't Hart, L. M., Franks, Paul W., Balkau, B., Froguel, P., McCarthy, M. I., Laakso, M., Groop, L., Christensen, C., Brandslund, I., Lauritzen, T., Witte, D. R., Linneberg, A., Jorgensen, T., Hansen, T., Wang, J., Nielsen, R., Pedersen, O., Albrechtsen, A., Grarup, N., Li, Y., Sparso, T., Tian, G., Cao, H., Jiang, T., Kim, S. Y., Korneliussen, T., Li, Q., Nie, C., Wu, R., Skotte, L., Morris, A. P., Ladenvall, C., Cauchi, S., Stancakova, A., Andersen, G., Astrup, A., Banasik, K., Bennett, A. J., Bolund, L., Charpentier, G., Chen, Y., Dekker, J. M., Doney, A. S. F., Dorkhan, M., Forsen, T., Frayling, T. M., Groves, C. J., Gui, Y., Hallmans, Göran, Hattersley, A. T., He, K., Hitman, G. A., Holmkvist, J., Huang, S., Jiang, H., Jin, X., Justesen, J. M., Kristiansen, K., Kuusisto, J., Lajer, M., Lantieri, O., Li, W., Liang, H., Liao, Q., Liu, X., Ma, T., Ma, X., Manijak, M. P., Marre, M., Mokrosinski, J., Morris, A. D., Mu, B., Nielsen, A. A., Nijpels, G., Nilsson, P., Palmer, C. N. A., Rayner, N. W., Renstrom, F., Ribel-Madsen, R., Robertson, N., Rolandsson, Olov, Rossing, P., Schwartz, T. W., Slagboom, P. E., Sterner, M., Tang, M., Tarnow, L., Tuomi, T., van't Riet, E., van Leeuwen, N., Varga, T. V., Vestmar, M. A., Walker, M., Wang, B., Wang, Y., Wu, H., Xi, F., Yengo, L., Yu, C., Zhang, X., Zhang, J., Zhang, Q., Zhang, W., Zheng, H., Zhou, Y., Altshuler, D., 't Hart, L. M., Franks, Paul W., Balkau, B., Froguel, P., McCarthy, M. I., Laakso, M., Groop, L., Christensen, C., Brandslund, I., Lauritzen, T., Witte, D. R., Linneberg, A., Jorgensen, T., Hansen, T., Wang, J., Nielsen, R., and Pedersen, O.
Abstract: Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) > 1% with common metabolic phenotypes. The study comprised three stages. We performed medium-depth (8x) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI > 27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case-control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. Exome sequencing identified 70,182 polymorphisms with MAF > 1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 x 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 x 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 x 10(-10)). We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.
Published: 2013
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19. An Aboriginal Australian genome reveals separate human dispersals into Asia

Author: Rasmussen, M., Guo, X., Wang, Y., Lohmueller, K.E., Rasmussen, S., Albrechtsen, A., Skotte, L., Lindgreen, S., Metspalu, M., Jombart, T., Kivisild, T., Zhai, W., Eriksson, A., Manica, A., Orlando, L., De La Vega, F.M., Tridico, S., Metspalu, E., Nielsen, K., Avila-Arcos, M.C., Moreno-Mayar, J.V., Muller, C., Dortch, J., Gilbert, M.T.P., Lund, O., Wesolowska, A., Karmin, M., Weinert, L.A., Wang, B., Li, J., Tai, S., Xiao, F., Hanihara, T., van Driem, G., Jha, A.R., Ricaut, F-X., de Knijff, P., Migliano, A.B., Gallego Romero, I., Kristiansen, K., Lambert, D.M., Brunak, S., Forster, P., Brinkmann, B., Nehlich, O., Bunce, M., Richards, M., Gupta, R., Bustamante, C.D., Krogh, A., Foley, R.A., Lahr, M.M., Balloux, F., Sicheritz-Ponten, T., Villems, R., Nielsen, R., Wang, J., Willerslev, E., Rasmussen, M., Guo, X., Wang, Y., Lohmueller, K.E., Rasmussen, S., Albrechtsen, A., Skotte, L., Lindgreen, S., Metspalu, M., Jombart, T., Kivisild, T., Zhai, W., Eriksson, A., Manica, A., Orlando, L., De La Vega, F.M., Tridico, S., Metspalu, E., Nielsen, K., Avila-Arcos, M.C., Moreno-Mayar, J.V., Muller, C., Dortch, J., Gilbert, M.T.P., Lund, O., Wesolowska, A., Karmin, M., Weinert, L.A., Wang, B., Li, J., Tai, S., Xiao, F., Hanihara, T., van Driem, G., Jha, A.R., Ricaut, F-X., de Knijff, P., Migliano, A.B., Gallego Romero, I., Kristiansen, K., Lambert, D.M., Brunak, S., Forster, P., Brinkmann, B., Nehlich, O., Bunce, M., Richards, M., Gupta, R., Bustamante, C.D., Krogh, A., Foley, R.A., Lahr, M.M., Balloux, F., Sicheritz-Ponten, T., Villems, R., Nielsen, R., Wang, J., and Willerslev, E.
Abstract: We present an Aboriginal Australian genomic sequence obtained from a 100-year-old lock of hair donated by an Aboriginal man from southern Western Australia in the early 20th century. We detect no evidence of European admixture and estimate contamination levels to be below 0.5%. We show that Aboriginal Australians are descendants of an early human dispersal into eastern Asia, possibly 62,000 to 75,000 years ago. This dispersal is separate from the one that gave rise to modern Asians 25,000 to 38,000 years ago. We also find evidence of gene flow between populations of the two dispersal waves prior to the divergence of Native Americans from modern Asian ancestors. Our findings support the hypothesis that present-day Aboriginal Australians descend from the earliest humans to occupy Australia, likely representing one of the oldest continuous populations outside Africa.
Published: 2011

20. The role of miRNAs in human papilloma virus (HPV)-associated cancers: bridging between HPV-related head and neck cancer and cervical cancer

Author: Lajer, C B, primary, Garnæs, E, additional, Friis-Hansen, L, additional, Norrild, B, additional, Therkildsen, M H, additional, Glud, M, additional, Rossing, M, additional, Lajer, H, additional, Svane, D, additional, Skotte, L, additional, Specht, L, additional, Buchwald, C, additional, and Nielsen, F C, additional
Published: 2012
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21. 288 Familial Aggregation and Heritability of Pyloric Stenosis

Author: Krogh, C, primary, Fischer, T, additional, Skotte, L, additional, Biggar, R J, additional, Øyen, N, additional, Skytthe, A, additional, Goertz, S, additional, Christensen, K, additional, Wohlfahrt, J, additional, and Melbye, M, additional
Published: 2010
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22. The role of miRNAs in human papilloma virus (HPV)-associated cancers: bridging between HPV-related head and neck cancer and cervical cancer.

Author: Lajer, C B, Garnæs, E, Friis-Hansen, L, Norrild, B, Therkildsen, M H, Glud, M, Rossing, M, Lajer, H, Svane, D, Skotte, L, Specht, L, Buchwald, C, Nielsen, F C, and Garnæs, E
Abstract: This corrects the article DOI: 10.1038/bjc.2012.109. [ABSTRACT FROM AUTHOR]
Published: 2017
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23. FAMILIAL AGGREGATION AND HERITABILITY OF PYLORIC STENOSIS

Author: Krogh, C., Fischer, T., Skotte, L., Biggar, R. J., Øyen, N., Skytthe, A., Goertz, S., Christensen, K., Wohlfahrt, J., and Melbye, M.
Published: 2010

24. Associations of autozygosity with a broad range of human phenotypes

Author: Dennis O. Mook-Kanamori, Salma M. Wakil, Lisa R. Yanek, Dominique P.V. de Kleijn, Gert J. de Borst, Alison D. Murray, Kamran Guity, Vincent W. V. Jaddoe, Mario Pirastu, Carole Ober, Giuseppe Matullo, Charles N. Rotimi, Daniela Ruggiero, Teresa Tusié-Luna, Wolfgang Lieb, Chew-Kiat Heng, John R. B. Perry, Hortensia Moreno-Macías, Jie Zhou, John M. Starr, Juhani Junttila, Lei Yu, Danielle Posthuma, Marcus Dörr, Yingchang Lu, Jonathan P. Bradfield, Einat Granot-Hershkovitz, Karina Meidtner, Wouter van Rheenen, T Esko, Maris Alver, Wen-Jane Lee, Zhengming Chen, Jennifer A. Brody, Paolo Gasparini, Yii-Der Ida Chen, Cinzia Sala, Peter P. Pramstaller, Gauri Prasad, Nana Matoba, Natalie Terzikhan, Simonetta Guarrera, Bjarke Feenstra, Peter Vollenweider, Smeeta Shrestha, Yi-Jen Hung, Lilja Stefansdottir, David R. Weir, Felix R. Day, Antonietta Robino, Liang Zhang, Lluis Quintana-Murci, Nicholas J. Timpson, Robyn E Wootton, Xue W. Mei, Dharambir K. Sanghera, Gisli Masson, Debbie A Lawlor, Thomas Meitinger, Sharon L.R. Kardia, Peter K. Joshi, Frank J. A. van Rooij, Claude Bouchard, Cassandra N. Spracklen, Ken K. Ong, Taulant Muka, Guanjie Chen, Laura J. Scott, Walter Palmas, Daniel I. Chasman, Sarah E. Medland, Krista Fischer, Blair H. Smith, Jon K. Sigurdsson, Leon Straker, Clara Viberti, Yuan Shi, Louis Pérusse, Peter J. van der Most, Timo Tõnis Sikka, Chris Haley, Kuang Lin, Leif Groop, Hester M. den Ruijter, Hakon Hakonarson, Masato Akiyama, Stephan J. L. Bakker, Sonja I. Berndt, Jeffery R. O'Connell, Cisca Wijmenga, Daniele Cusi, Lorena Orozco, Kristjan H. S. Moore, Kevin Sandow, Stephen S. Rich, Stephanie J. Loomis, George Davey Smith, Cornelia M. van Duijn, Sharvari Rahul Shukla, Agnar Helgason, Thorsten Kessler, Anuj Goel, Dan Mason, David W. Clark, James S. Pankow, Simona Vaccargiu, Uwe Völker, Tamara B. Harris, Matthew A. Allison, Clicerio Gonzalez, Sarju Ralhan, I-Te Lee, Matthias Laudes, Yen-Feng Chiu, Neil Poulter, Benjamin Lehne, John Wright, Lawrence F. Bielak, Philip L. De Jager, Reinhold Schmidt, Ya Xing Wang, Matthias Nauck, Diana L. Cousminer, Patrick Deelen, Ani Manichaikul, Stephen J. Chanock, Anders Hamsten, Barry I. Freedman, Gudmar Thorleifsson, Peter Kraft, Ozren Polasek, Jie Yao, Yoshinori Murakami, Paul M. Ridker, Anubha Mahajan, Struan F.A. Grant, Claudia Schurmann, Bjarni Gunnarsson, Catriona L. K. Barnes, Jessica van Setten, Sandosh Padmanabhan, Alena Stančáková, Markus M. Lerch, Anuradha Jagadeesan, Franco Giulianini, Daniel F. Gudbjartsson, Dwaipayan Bharadwaj, Shengchao Alfred Li, Peter S. Sever, Trevor A. Mori, Albertine J. Oldehinkel, Koichi Matsuda, Xueling Sim, Evangelos Evangelou, André G. Uitterlinden, Pekka Jousilahti, Yukihide Momozawa, Ioanna Tzoulaki, Chao A. Hsiung, Ginevra Biino, Murielle Bochud, Hannele Mattsson, Ilja M. Nolte, Sarah H. Wild, Patricia B. Munroe, Jianjun Liu, Bruce M. Psaty, Giriraj R. Chandak, Masahiro Kanai, Tony R. Merriman, Teemu Palviainen, Rodney A. Lea, Janie Corley, Nicholas J. Wareham, Alan B. Zonderman, Makoto Hirata, Matthew J. Bixley, Caroline Hayward, Nora Franceschini, Kristel R van Eijk, Etienne Patin, Daniel Shriner, Niek Verweij, Xiuqing Guo, Fredrik Karpe, Ruth J. F. Loos, Tiinamaija Tuomi, Ashley van der Spek, Patricia A. Peyser, Jessica D. Faul, Christian Fuchsberger, David Cesarini, Alex S. F. Doney, Janine F. Felix, Cornelius A. Rietveld, Jagadish Vangipurapu, Tanguy Corre, Line Skotte, Rajkumar Dorajoo, Catherine Igartua, Meena Kumari, Nona Sotoodehnia, Leonard H. van den Berg, Najaf Amin, Dale R. Nyholt, Harry Campbell, Massimiliano Cocca, Scott D. Gordon, Patrik K. E. Magnusson, John C. Chambers, Traci M. Bartz, Mike A. Nalls, Tin Aung, Nduna Dzimiri, Colin N. A. Palmer, Rob M. van Dam, Johanna Kuusisto, Russell P. Tracy, Anna Damulina, Pierre-Emmanuel Morange, Sylvain Foisy, Jing Hua Zhao, Nicholas G. Martin, Ching-Yu Cheng, Mariaelisa Graff, Rashmi B. Prasad, Alice Stanton, David-Alexandre Trégouët, Yu Guo, Helen R. Warren, Lyn R. Griffiths, Weihua Meng, Annika Tillander, Christa Meisinger, Albert V. Smith, Mark I. McCarthy, Jingyun Yang, Marine Germain, Neil Small, Linda Broer, Vilmundur Gudnason, Gunnar K. Pálsson, Michele K. Evans, Alexander Teumer, Mark J. Caulfield, Giorgia Girotto, Thomas Lumley, Tinca J. C. Polderman, Wei Zhao, Carlos A. Aguilar-Salinas, Jari Lahti, Matthew L. Albert, Yechiel Friedlander, Veikko Salomaa, Iona Y Millwood, Jan H. Veldink, Archie Campbell, Andres Metspalu, Ulf Gyllensten, Grant W. Montgomery, Veronique Vitart, Jai Rup Singh, Saima Afaq, Alan R. Shuldiner, Miao-Li Chee, Adebowale Adeyemo, Jennifer A. Smith, David A. van Heel, Jaspal S. Kooner, Daniela Toniolo, Cristian Pattaro, Jerome I. Rotter, John Whitfield, Melissa C. Smart, Kari E. North, Salman M. Tajuddin, Tallapragada Divya Sri Priyanka, Christopher A. Haiman, Diane M. Becker, Bernhard K. Krämer, Paul Elliott, Lihua Wang, He Gao, Patrick Sulem, Jinyan Huang, Chiea Chuen Khor, Ruifang Li-Gao, Åsa Johansson, Winfried März, Shai Carmi, Ilaria Gandin, Eric Boerwinkle, Gardar Sveinbjornsson, Saskia P. Hagenaars, Sander W. van der Laan, Gerard Pasterkamp, E-Shyong Tai, Hagit Hochner, Yih Chung Tham, Kent D. Taylor, Kari Stefansson, Matt J. Neville, Craig E. Pennell, Yanchun Bao, Annelot M. Dekker, Helena Schmidt, Mehdi Hedayati, Joshua Elliott, Ian J. Deary, Iris E. Jansen, Judith B. Borja, Edith Hofer, Martin Gögele, Igor Rudan, Lude Franke, Matthias Munz, Folkert W. Asselbergs, Bengt Sennblad, Imo Hofer, John D. Rioux, Pim van der Harst, Bahareh Sedaghati-khayat, Giovanni Cugliari, Morris A. Swertz, Francine Grodstein, Erwin P. Bottinger, Carol A. Wang, Andre Franke, Brian F. Meyer, Adele M. Taylor, Klodian Dhana, Jian'an Luan, Constance Turman, Robert A. Scott, May E. Montasser, Alison Pattie, Marco Brumat, Liming Li, Heiner Boeing, Karen L. Mohlke, Clemens Baumbach, Bishwa Raj Sapkota, Unnur Thorsteinsdottir, Naveed Sattar, Amy R. Bentley, Matthias B. Schulze, Ivana Kolcic, Stella Trompet, Sarah E. Harris, Ayo P. Doumatey, Charumathi Sabanayagam, David Eccles, Mary F. Feitosa, Jost B. Jonas, Massimo Mezzavilla, Mark O. Goodarzi, David Ellinghaus, Heribert Schunkert, Christian Gieger, Heikki V. Huikuri, Lingyao Zeng, Johan G. Eriksson, Woon-Puay Koh, Yucheng Jia, Gurpreet Singh Wander, James F. Wilson, Torgny Karlsson, Steven C. Hunt, Weihua Zhang, Maria Pina Concas, Zoltán Kutalik, Rebecca Rohde, Chittaranjan S. Yajnik, Yasaman Saba, Dabeeru C. Rao, Robin G. Walters, Reedik Mägi, Marie Loh, Eero Vuoksimaa, Josyf C. Mychaleckyj, Katri Räikkönen, Philippe Goyette, M. Arfan Ikram, Alicia Huerta-Chagoya, David J. Porteous, Teresa Nutile, J. Wouter Jukema, Noha A. Yousri, Yoichiro Kamatani, Maryam S. Daneshpour, Babette S. Zemel, Rona J. Strawbridge, Tien Yin Wong, Claudia Langenberg, Amy Moore, Marcus E. Kleber, Fereidoun Azizi, Avner Halevy, Erika Salvi, Francis S. Collins, Markku Laakso, Tim Kacprowski, S. Sunna Ebenesersdóttir, William R. Scott, Michael Boehnke, Jin-Fang Chai, Markus Perola, Nicola Pirastu, Wayne Huey-Herng Sheu, Robert Karlsson, Lenore J. Launer, Lili Milani, Renée de Mutsert, Fernando Rivadeneira, David A. Bennett, Nicola D. Kerrison, Paolo Manunta, Graciela E. Delgado, Magnus Johannesson, Carolina Medina-Gomez, Alanna C. Morrison, Kay-Tee Khaw, Jian-Min Yuan, Jaakko Kaprio, Melanie Waldenberger, Ralf Ewert, Hugoline G. de Haan, Andrew A. Hicks, Yukinori Okada, Maria Sabater-Lleal, Marilyn C. Cornelis, Stephanie J. London, Federica Rizzi, Jeanette Erdmann, Marina Ciullo, Michiaki Kubo, University of Edinburgh, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Osaka University Graduate School of Medicine, Laboratory for Cardiovascular Genomics and Informatics [Yokohama] (RIKEN IMS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN)-RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), deCODE genetics [Reykjavik], Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK (BIHR), Area Science Park, Università degli studi di Trieste = University of Trieste, MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Harbor UCLA Medical Center [Torrance, Ca.], Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, Department of Electrical and Computer Engineering [Waterloo] (ECE), University of Waterloo [Waterloo], Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Institute of Pop. Genetics, CNR, Sassari, Shardna life science Pula Cagliari, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Medstar Research Institute, Florida State University [Tallahassee] (FSU), University Medical Center [Utrecht], Centre for Population Health Sciences, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), California State University [Sacramento], Department of Thrombosis and Haemostasis, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Medical University Graz, Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Heidelberg, Frederick National Laboratory for Cancer Research (FNLCR), Wellcome Trust Centre of Human Genetics, University of Oxford, Department of Epidemiology, German Institute of Human Nutrition, University Medical Center Groningen [Groningen] (UMCG), Institute of Genetics and Biophysics, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Department of Medicine, Surgery, and Dentistry, University of Milano, Icelandic Heart Association, Kopavogur, Iceland., Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Glasgow, Department of Cardiology, Leiden University Medical Center, Leiden, Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, Queen Mary University of London (QMUL), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Institut de biologie moléculaire des plantes (IBMP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Genentech, Inc., Genentech, Inc. [San Francisco], University of Tartu, Duke-NUS Medical School [Singapore], Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association, Human Genome Sequencing Center, Baylor College of Medicine, Baylor College of Medicine (BCM), Baylor University-Baylor University, University of San Carlos, Office of Population Studies Foundation, Icahn School of Medicine at Mount Sinai [New York] (MSSM), King‘s College London, Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), University of Oxford, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Department of Internal Medicine B, University Medicine Greifswald, Greifswald, University of Chicago, University of Huddersfield, Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Section on Nephrology [Winston-Salem, NC, USA] (Department of Internal Medicine), Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center-Wake Forest Baptist Medical Center, Radcliffe Department of Medicine [Oxford], Harvard School of Public Health, Kunming University of Science and Technology (KMUST), Sans affiliation, University of Southern California (USC), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), MRC Centrer for Nutritional Epidemiology and Cancer Prevention and Survival, University of Cambridge [UK] (CAM), National University of Singapore (NUS), Experimental Cardiology Laboratory (ECL), Unirversity Medical Center, Department of Medical Statistics, Epidemiology and Medical Informatics, University of Zagreb, Department of Medical Genetics, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Capital Normal University [Beijing], Saw Swee Hock School of Public Health, National Institute for Environmental Health Sciences Research Triangle Park, Brown University, MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, Toyota Research Institute, Helmholtz Zentrum München = German Research Center for Environmental Health, Department of Chemistry and Biochemistry [Boulder], University of Colorado [Boulder], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de la Timone [CHU - APHM] (TIMONE), Metacohorts Consortium, Universiteit Leiden, Institute of Clinical Chemistry and Laboratory Medicine, University of Groningen [Groningen], Medical Research Concil Epidemiology Unit, Institute of Medical Science, Faculty of Medicine, Genetics and Pathology, Imperial College London, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Brigham and Women's Hospital [Boston], Erasmus University Rotterdam, Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Stockholm Bioinformatics Center (SBC), Stockholm University, Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, INRH, Department of Genetics, Los Angeles Biomedical Research Institute (LA BioMed), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán - National Institute of Medical Science and Nutrition Salvador Zubiran [Mexico], Western General Hospital, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Medical Research Council, Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute-University of Pittsburgh Graduate School of Public Health, Zhengzhou University of Light Industry, Department of Electrical and Electronic Engineering [Niigata Univ.], Niigata University, Genetic Epidemiology Unit, University College of London [London] (UCL), Aston Business School, Aston University [Birmingham], Division of Cancer Epidemiology and Genetics [Bethesda, MD, États-Unis], Centre Hospitalier Universitaire Vaudois (CHUV), Pennington Biomedical Research Center, University of Washington [Seattle], Guy's and St Thomas' Hospitals, Northwestern Polytechnical University [Xi'an] (NPU), Department of Social Medicine, University of Bristol [Bristol], Department of Genomics of Common Disease [London, UK], Imperial College London-Hammersmith Hospital NHS Imperial College Healthcare, Department of Internal Medicine, Institute of Clinical Molecular Biology, Kiel University, Medizinische Klinik II, Universität zu Lübeck = University of Lübeck [Lübeck], Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina, Institute for Social Research, University of Michigan System-University of Michigan System, Division of Statistical Genomics, Washington University School of Medicine, Institute for Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel (CAU), Department of Physics, RISSC-Lab-University of Naples Federico II = Università degli studi di Napoli Federico II, Lund University [Lund], Icelandic Heart Association, Heart Preventive Clinic and Research Institute, The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Medical Research Center Oulu, University of Oulu, University of Utah School of Medicine [Salt Lake City], The Generation R Study, Pediatrics, Epidemiology, Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis] (CTCN), Department of Neurology [New York, NY, États-Unis], Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York]-Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York], Universität Heidelberg [Heidelberg] = Heidelberg University, Interuniversity Cardiology Institute Netherlands, School of Public Health, University of Michigan [Dearborn], Department of Epidemiology and Public Health, University of Kuopio, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Epidemiology and Biobank PopGen, Department of Biostatistics, University of Washington, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Clinical Institute of Medical and Chemical Laboratory Diagnostics, Karl-Franzens-Universität Graz, Department of Genetics, Biology and Biochemistry, Università degli studi di Torino = University of Turin (UNITO), Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), QIMR Berghofer Medical Research Institute, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, University of Illinois [Chicago] (UIC), University of Illinois System, Experimental Cardiology Laboratory, Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Functional Genomics, Erasmus Medical Centre, National Human Genome Research Institute (NHGRI), School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Department of Pathological Biochemistry, Royal Infirmary, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Institute of Metabolic Science, MRC, University of Maryland School of Medicine [Baltimore, MD, USA], Centre for Molecular Epidemiology, Centre for Causal Analyses in Translational Epidemiology, University of Bristol [Bristol]-Medical Research Council, IRCCS San Raffaele Scientific Institute [Milan, Italie], U937, Génomique cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), University of Michigan System, HMNC Brain Health, Singapore Eye Research Institute, Partenaires INRAE, Institut d'Électronique et des Technologies du numéRique (IETR), Université de Nantes (UN)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Department of Psychiatry and Psychotherapy, Rheinische Friedrich-Wilhelms-Universität Bonn, University of Groningen, Department of Genomics of Common Disease, Department of Microbiology, The Freeman Hospital, Department Biostatistics University of North Carolina, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Clark, D. W., Okada, Y., Moore, K. H. S., Mason, D., Pirastu, N., Gandin, I., Mattsson, H., Barnes, C. L. K., Lin, K., Zhao, J. H., Deelen, P., Rohde, R., Schurmann, C., Guo, X., Giulianini, F., Zhang, W., Medina-Gomez, C., Karlsson, R., Bao, Y., Bartz, T. M., Baumbach, C., Biino, G., Bixley, M. J., Brumat, M., Chai, J. -F., Corre, T., Cousminer, D. L., Dekker, A. M., Eccles, D. A., van Eijk, K. R., Fuchsberger, C., Gao, H., Germain, M., Gordon, S. D., de Haan, H. G., Harris, S. E., Hofer, E., Huerta-Chagoya, A., Igartua, C., Jansen, I. E., Jia, Y., Kacprowski, T., Karlsson, T., Kleber, M. E., Li, S. A., Li-Gao, R., Mahajan, A., Matsuda, K., Meidtner, K., Meng, W., Montasser, M. E., van der Most, P. J., Munz, M., Nutile, T., Palviainen, T., Prasad, G., Prasad, R. B., Priyanka, T. D. S., Rizzi, F., Salvi, E., Sapkota, B. R., Shriner, D., Skotte, L., Smart, M. C., Smith, A. V., van der Spek, A., Spracklen, C. N., Strawbridge, R. J., Tajuddin, S. M., Trompet, S., Turman, C., Verweij, N., Viberti, C., Wang, L., Warren, H. R., Wootton, R. E., Yanek, L. R., Yao, J., Yousri, N. A., Zhao, W., Adeyemo, A. A., Afaq, S., Aguilar-Salinas, C. A., Akiyama, M., Albert, M. L., Allison, M. A., Alver, M., Aung, T., Azizi, F., Bentley, A. R., Boeing, H., Boerwinkle, E., Borja, J. B., de Borst, G. J., Bottinger, E. P., Broer, L., Campbell, H., Chanock, S., Chee, M. -L., Chen, G., Chen, Y. -D. I., Chen, Z., Chiu, Y. -F., Cocca, M., Collins, F. S., Concas, M. P., Corley, J., Cugliari, G., van Dam, R. M., Damulina, A., Daneshpour, M. S., Day, F. R., Delgado, G. E., Dhana, K., Doney, A. S. F., Dorr, M., Doumatey, A. P., Dzimiri, N., Ebenesersdottir, S. S., Elliott, J., Elliott, P., Ewert, R., Felix, J. F., Fischer, K., Freedman, B. I., Girotto, G., Goel, A., Gogele, M., Goodarzi, M. O., Graff, M., Granot-Hershkovitz, E., Grodstein, F., Guarrera, S., Gudbjartsson, D. F., Guity, K., Gunnarsson, B., Guo, Y., Hagenaars, S. P., Haiman, C. A., Halevy, A., Harris, T. B., Hedayati, M., van Heel, D. A., Hirata, M., Hofer, I., Hsiung, C. A., Huang, J., Hung, Y. -J., Ikram, M. A., Jagadeesan, A., Jousilahti, P., Kamatani, Y., Kanai, M., Kerrison, N. D., Kessler, T., Khaw, K. -T., Khor, C. C., de Kleijn, D. P. V., Koh, W. -P., Kolcic, I., Kraft, P., Kramer, B. K., Kutalik, Z., Kuusisto, J., Langenberg, C., Launer, L. J., Lawlor, D. A., Lee, I. -T., Lee, W. -J., Lerch, M. M., Li, L., Liu, J., Loh, M., London, S. J., Loomis, S., Lu, Y., Luan, J., Magi, R., Manichaikul, A. W., Manunta, P., Masson, G., Matoba, N., Mei, X. W., Meisinger, C., Meitinger, T., Mezzavilla, M., Milani, L., Millwood, I. Y., Momozawa, Y., Moore, A., Morange, P. -E., Moreno-Macias, H., Mori, T. A., Morrison, A. C., Muka, T., Murakami, Y., Murray, A. D., de Mutsert, R., Mychaleckyj, J. C., Nalls, M. A., Nauck, M., Neville, M. J., Nolte, I. M., Ong, K. K., Orozco, L., Padmanabhan, S., Palsson, G., Pankow, J. S., Pattaro, C., Pattie, A., Polasek, O., Poulter, N., Pramstaller, P. P., Quintana-Murci, L., Raikkonen, K., Ralhan, S., Rao, D. C., van Rheenen, W., Rich, S. S., Ridker, P. M., Rietveld, C. A., Robino, A., van Rooij, F. J. A., Ruggiero, D., Saba, Y., Sabanayagam, C., Sabater-Lleal, M., Sala, C. F., Salomaa, V., Sandow, K., Schmidt, H., Scott, L. J., Scott, W. R., Sedaghati-Khayat, B., Sennblad, B., van Setten, J., Sever, P. J., Sheu, W. H. -H., Shi, Y., Shrestha, S., Shukla, S. R., Sigurdsson, J. K., Sikka, T. T., Singh, J. R., Smith, B. H., Stancakova, A., Stanton, A., Starr, J. M., Stefansdottir, L., Straker, L., Sulem, P., Sveinbjornsson, G., Swertz, M. A., Taylor, A. M., Taylor, K. D., Terzikhan, N., Tham, Y. -C., Thorleifsson, G., Thorsteinsdottir, U., Tillander, A., Tracy, R. P., Tusie-Luna, T., Tzoulaki, I., Vaccargiu, S., Vangipurapu, J., Veldink, J. H., Vitart, V., Volker, U., Vuoksimaa, E., Wakil, S. M., Waldenberger, M., Wander, G. S., Wang, Y. X., Wareham, N. J., Wild, S., Yajnik, C. S., Yuan, J. -M., Zeng, L., Zhang, L., Zhou, J., Amin, N., Asselbergs, F. W., Bakker, S. J. L., Becker, D. M., Lehne, B., Bennett, D. A., van den Berg, L. H., Berndt, S. I., Bharadwaj, D., Bielak, L. F., Bochud, M., Boehnke, M., Bouchard, C., Bradfield, J. P., Brody, J. A., Campbell, A., Carmi, S., Caulfield, M. J., Cesarini, D., Chambers, J. C., Chandak, G. R., Cheng, C. -Y., Ciullo, M., Cornelis, M., Cusi, D., Smith, G. D., Deary, I. J., Dorajoo, R., van Duijn, C. M., Ellinghaus, D., Erdmann, J., Eriksson, J. G., Evangelou, E., Evans, M. K., Faul, J. D., Feenstra, B., Feitosa, M., Foisy, S., Franke, A., Friedlander, Y., Gasparini, P., Gieger, C., Gonzalez, C., Goyette, P., Grant, S. F. A., Griffiths, L. R., Groop, L., Gudnason, V., Gyllensten, U., Hakonarson, H., Hamsten, A., van der Harst, P., Heng, C. -K., Hicks, A. A., Hochner, H., Huikuri, H., Hunt, S. C., Jaddoe, V. W. V., De Jager, P. L., Johannesson, M., Johansson, A., Jonas, J. B., Jukema, J. W., Junttila, J., Kaprio, J., Kardia, S. L. R., Karpe, F., Kumari, M., Laakso, M., van der Laan, S. W., Lahti, J., Laudes, M., Lea, R. A., Lieb, W., Lumley, T., Martin, N. G., Marz, W., Matullo, G., Mccarthy, M. I., Medland, S. E., Merriman, T. R., Metspalu, A., Meyer, B. F., Mohlke, K. L., Montgomery, G. W., Mook-Kanamori, D., Munroe, P. B., North, K. E., Nyholt, D. R., O'Connell, J. R., Ober, C., Oldehinkel, A. J., Palmas, W., Palmer, C., Pasterkamp, G. G., Patin, E., Pennell, C. E., Perusse, L., Peyser, P. A., Pirastu, M., Polderman, T. J. C., Porteous, D. J., Posthuma, D., Psaty, B. M., Rioux, J. D., Rivadeneira, F., Rotimi, C., Rotter, J. I., Rudan, I., Den Ruijter, H. M., Sanghera, D. K., Sattar, N., Schmidt, R., Schulze, M. B., Schunkert, H., Scott, R. A., Shuldiner, A. R., Sim, X., Small, N., Smith, J. A., Sotoodehnia, N., Tai, E. -S., Teumer, A., Timpson, N. J., Toniolo, D., Tregouet, D. -A., Tuomi, T., Vollenweider, P., Wang, C. A., Weir, D. R., Whitfield, J. B., Wijmenga, C., Wong, T. -Y., Wright, J., Yang, J., Yu, L., Zemel, B. S., Zonderman, A. B., Perola, M., Magnusson, P. K. E., Uitterlinden, A. G., Kooner, J. S., Chasman, D. I., Loos, R. J. F., Franceschini, N., Franke, L., Haley, C. S., Hayward, C., Walters, R. G., Perry, J. R. B., Esko, T., Helgason, A., Stefansson, K., Joshi, P. K., Kubo, M., Wilson, J. F., Læknadeild (HÍ), Faculty of Medicine (UI), Félagsfræði-, mannfræði- og þjóðfræðideild (HÍ), Faculty of Sociology, Anthropology and Folkloristics (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Félagsvísindasvið (HÍ), School of Social Sciences (UI), Háskóli Íslands, University of Iceland, Clark, David W [0000-0002-1025-9185], Okada, Yukinori [0000-0002-0311-8472], Moore, Kristjan H S [0000-0002-9579-4362], Mason, Dan [0000-0002-0026-9216], Pirastu, Nicola [0000-0002-5363-3886], Gandin, Ilaria [0000-0003-3196-2491], Deelen, Patrick [0000-0002-5654-3966], Schurmann, Claudia [0000-0003-4158-9192], Medina-Gomez, Carolina [0000-0001-7999-5538], Karlsson, Robert [0000-0002-8949-2587], Bao, Yanchun [0000-0002-6102-5098], Biino, Ginevra [0000-0002-9936-946X], Brumat, Marco [0000-0003-3268-039X], Chai, Jin-Fang [0000-0003-3770-1137], Eccles, David A [0000-0003-4634-4995], Gordon, Scott D [0000-0001-7623-328X], Harris, Sarah E [0000-0002-4941-5106], Kacprowski, Tim [0000-0002-5393-2413], Karlsson, Torgny [0000-0001-8095-6149], Kleber, Marcus E [0000-0003-0663-7275], Mahajan, Anubha [0000-0001-5585-3420], Matsuda, Koichi [0000-0001-7292-2686], Meng, Weihua [0000-0001-5388-8494], van der Most, Peter J [0000-0001-8450-3518], Munz, Matthias [0000-0002-4728-3357], Palviainen, Teemu [0000-0002-7847-8384], Prasad, Rashmi B [0000-0002-4400-6741], Salvi, Erika [0000-0002-2724-2291], Skotte, Line [0000-0002-7398-1271], van der Spek, Ashley [0000-0001-7136-0159], Spracklen, Cassandra N [0000-0003-3590-7182], Strawbridge, Rona J [0000-0001-8506-3585], Tajuddin, Salman M [0000-0002-7919-8528], Verweij, Niek [0000-0002-4303-7685], Yanek, Lisa R [0000-0001-7117-1075], Zhao, Wei [0000-0001-7388-0692], Albert, Matthew L [0000-0001-7285-6973], Bentley, Amy R [0000-0002-0827-9101], Chanock, Stephen [0000-0002-2324-3393], Chen, Zhengming [0000-0001-6423-105X], Chiu, Yen-Feng [0000-0002-3352-4500], Cocca, Massimiliano [0000-0002-1127-7596], Collins, Francis S [0000-0002-1023-7410], Cugliari, Giovanni [0000-0002-6080-0718], Damulina, Anna [0000-0001-8241-2727], Day, Felix R [0000-0003-3789-7651], Dhana, Klodian [0000-0002-6397-7009], Dzimiri, Nduna [0000-0003-3395-5754], Elliott, Paul [0000-0002-7511-5684], Felix, Janine F [0000-0002-9801-5774], Freedman, Barry I [0000-0003-0275-5530], Girotto, Giorgia [0000-0003-4507-6589], Goel, Anuj [0000-0003-2307-4021], Goodarzi, Mark O [0000-0001-6364-5103], Gudbjartsson, Daniel F [0000-0002-5222-9857], Guity, Kamran [0000-0002-8379-9668], van Heel, David A [0000-0002-0637-2265], Hirata, Makoto [0000-0002-9994-9958], Ikram, M Arfan [0000-0003-0372-8585], Kamatani, Yoichiro [0000-0001-8748-5597], Kanai, Masahiro [0000-0001-5165-4408], Khor, Chiea Chuen [0000-0002-1128-4729], Kolcic, Ivana [0000-0001-7918-6052], Langenberg, Claudia [0000-0002-5017-7344], Lawlor, Deborah A [0000-0002-6793-2262], Liu, Jianjun [0000-0002-3255-3019], London, Stephanie J [0000-0003-4911-5290], Luan, Jian’an [0000-0003-3137-6337], Matoba, Nana [0000-0001-5329-0134], Mei, Xue W [0000-0002-6279-4884], Mezzavilla, Massimo [0000-0002-9000-4595], Milani, Lili [0000-0002-5323-3102], Mori, Trevor A [0000-0002-5264-9229], Murakami, Yoshinori [0000-0002-2826-4396], Murray, Alison D [0000-0003-4915-4847], Mychaleckyj, Josyf C [0000-0003-2595-0005], Neville, Matt J [0000-0002-6004-5433], Nolte, Ilja M [0000-0001-5047-4077], Ong, Ken K [0000-0003-4689-7530], Pálsson, Gunnar [0000-0002-8231-3961], Pankow, James S [0000-0001-7076-483X], Pattaro, Cristian [0000-0002-4119-0109], Quintana-Murci, Lluis [0000-0003-2429-6320], van Rheenen, Wouter [0000-0002-5860-1533], Rich, Stephen S [0000-0003-3872-7793], Rietveld, Cornelius A [0000-0003-4053-1861], Ruggiero, Daniela [0000-0003-3898-7827], Sabanayagam, Charumathi [0000-0002-4042-4719], Sabater-Lleal, Maria [0000-0002-0128-379X], Sala, Cinzia Felicita [0000-0003-2514-2075], Salomaa, Veikko [0000-0001-7563-5324], Scott, Laura J [0000-0002-4886-5084], Sedaghati-Khayat, Bahareh [0000-0002-7665-8648], Sennblad, Bengt [0000-0002-4360-8003], van Setten, Jessica [0000-0002-4934-7510], Smith, Blair H [0000-0002-5362-9430], Stančáková, Alena [0000-0002-1375-0252], Stanton, Alice [0000-0002-4961-165X], Straker, Leon [0000-0002-7786-4128], Sulem, Patrick [0000-0001-7123-6123], Swertz, Morris A [0000-0002-0979-3401], Taylor, Kent D [0000-0002-2756-4370], Tzoulaki, Ioanna [0000-0002-4275-9328], Veldink, Jan H [0000-0001-5572-9657], Vitart, Veronique [0000-0002-4991-3797], Völker, Uwe [0000-0002-5689-3448], Wander, Gurpreet S [0000-0002-4596-4247], Wang, Ya Xing [0000-0003-2749-7793], Wild, Sarah [0000-0001-7824-2569], Yuan, Jian-Min [0000-0002-4620-3108], Asselbergs, Folkert W [0000-0002-1692-8669], Boehnke, Mike [0000-0002-6442-7754], Bouchard, Claude [0000-0002-0048-491X], Brody, Jennifer A [0000-0001-8509-148X], Campbell, Archie [0000-0003-0198-5078], Caulfield, Mark J [0000-0001-9295-3594], Smith, George Davey [0000-0002-1407-8314], Dorajoo, Rajkumar [0000-0001-6608-2051], Ellinghaus, David [0000-0002-4332-6110], Erdmann, Jeanette [0000-0002-4486-6231], Evangelou, Evangelos [0000-0002-5488-2999], Feenstra, Bjarke [0000-0003-1478-649X], Feitosa, Mary [0000-0002-0933-2410], Franke, Andre [0000-0003-1530-5811], Grant, Struan F A [0000-0003-2025-5302], Griffiths, Lyn R [0000-0002-6774-5475], Groop, Leif [0000-0002-0187-3263], Gudnason, Vilmundur [0000-0001-5696-0084], van der Harst, Pim [0000-0002-2713-686X], Heng, Chew-Kiat [0000-0002-7309-9473], Hicks, Andrew A [0000-0001-6320-0411], Jaddoe, Vincent W V [0000-0003-2939-0041], De Jager, Philip L [0000-0002-8057-2505], Johannesson, Magnus [0000-0001-8759-6393], Johansson, Åsa [0000-0002-2915-4498], Jonas, Jost B [0000-0003-2972-5227], Jukema, J Wouter [0000-0002-3246-8359], Kaprio, Jaakko [0000-0002-3716-2455], Laakso, Markku [0000-0002-3394-7749], van der Laan, Sander W [0000-0001-6888-1404], Lahti, Jari [0000-0002-4310-5297], Martin, Nicholas G [0000-0003-4069-8020], Medland, Sarah E [0000-0003-1382-380X], Merriman, Tony R [0000-0003-0844-8726], Metspalu, Andres [0000-0002-3718-796X], Mohlke, Karen L [0000-0001-6721-153X], Montgomery, Grant W [0000-0002-4140-8139], Munroe, Patricia B [0000-0002-4176-2947], Nyholt, Dale R [0000-0001-7159-3040], Ober, Carole [0000-0003-4626-9809], Oldehinkel, Albertine J [0000-0003-3925-3913], Palmer, Colin [0000-0002-6415-6560], Perusse, Louis [0000-0001-6440-9698], Polderman, Tinca J. C. [0000-0001-5564-301X], Porteous, David J [0000-0003-1249-6106], Rioux, John D [0000-0001-7560-8326], Rivadeneira, Fernando [0000-0001-9435-9441], Rotimi, Charles [0000-0001-5759-053X], Rotter, Jerome I [0000-0001-7191-1723], Rudan, Igor [0000-0001-6993-6884], Sattar, Naveed [0000-0002-1604-2593], Sim, Xueling [0000-0002-1233-7642], Smith, Jennifer A [0000-0002-3575-5468], Teumer, Alexander [0000-0002-8309-094X], Timpson, Nicholas J [0000-0002-7141-9189], Tuomi, Tiinamaija [0000-0002-8306-6202], Wang, Carol A [0000-0002-4301-3974], Weir, David R [0000-0002-1661-2402], Whitfield, John B [0000-0002-1103-0876], Magnusson, Patrik K. E. [0000-0002-7315-7899], Uitterlinden, André G [0000-0002-7276-3387], Loos, Ruth J. F. [0000-0002-8532-5087], Franke, Lude [0000-0002-5159-8802], Haley, Chris S [0000-0002-9811-0210], Hayward, Caroline [0000-0002-9405-9550], Walters, Robin G [0000-0002-9179-0321], Joshi, Peter K [0000-0002-6361-5059], Wilson, James F [0000-0001-5751-9178], Apollo - University of Cambridge Repository, Moore, Kristjan HS [0000-0002-9579-4362], Luan, Jian'an [0000-0003-3137-6337], Grant, Struan FA [0000-0003-2025-5302], Jaddoe, Vincent WV [0000-0003-2939-0041], Polderman, Tinca JC [0000-0001-5564-301X], Magnusson, Patrik KE [0000-0002-7315-7899], Loos, Ruth JF [0000-0002-8532-5087], Neurology, Human genetics, Amsterdam Reproduction & Development (AR&D), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Stem Cell Aging Leukemia and Lymphoma (SALL), Institute for Molecular Medicine Finland, Department of Psychology and Logopedics, University Management, Developmental Psychology Research Group, Staff Services, Cognitive and Brain Aging, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Clinicum, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Genetic Epidemiology, Helsinki Collegium for Advanced Studies, HUS Abdominal Center, Endokrinologian yksikkö, Bradford Teaching Hospitals NHS Foundation Trust [Bradford, UK] (BTHFT), University of Trieste, Université de Lausanne (UNIL), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Consiglio Nazionale delle Ricerche (CNR), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut Pasteur [Paris], University of Oxford [Oxford], Medical Genetics, Dept. RSD and Public Health, IRCCS-Burlo Garofolo/University of Trieste, sans affiliation, Helmholtz-Zentrum München (HZM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institute of Cardiovascular Science, University College London, Hammersmith Hospital NHS Imperial College Healthcare-Imperial College London, Universität zu Lübeck [Lübeck], University of Ioannina Medical School, Università degli studi di Napoli Federico II-RISSC-Lab, Universität Heidelberg [Heidelberg], University of Turin, University of California-University of California, Nantes Université (NU)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), University of Helsinki-University of Helsinki, Université de Nantes (UN)-Université de Rennes 1 (UR1), Erasmus MC other, Internal Medicine, and Applied Economics
Subjects: 0301 basic medicine, 631/208/1397, Chemistry(all), Health Status, [SDV]Life Sciences [q-bio], LOCI, General Physics and Astronomy, MESH: Haplotype, MESH: Cognition, 030105 genetics & heredity, Runs of Homozygosity, Biochemistry, Consanguinity, Cognition, Inbreeding depression, 2.1 Biological and endogenous factors, Body Size, Inbreeding, Skyldleikarækt, Aetiology, Human phenotypes, lcsh:Science, MESH: Health Status, Genetics, Multidisciplinary, Inbreeding Depression, Confounding, Homozygote, RUNS, 631/208/205, 631/208/721, 3. Good health, genomic inbreeding coefficients, MESH: Risk-Taking, 631/208/730, Autozygosit, homozygosity, Erfðarannsóknir, Medical Genetics, genomic inbreeding coefficient, MESH: Homozygote, Offspring, Science, Autozygosity, Blóðsifjar, 610 Medicine & health, Biology, INBREEDING DEPRESSION, HOMOZYGOSITY, FERTILITY, QUANTIFICATION, Physics and Astronomy(all), General Biochemistry, Genetics and Molecular Biology, Article, Association, 03 medical and health sciences, Risk-Taking, 360 Social problems & social services, Journal Article, Humans, ddc:610, Allele, Alleles, Medicinsk genetik, Genetic association study, MESH: Consanguinity, MESH: Body Size, MESH: Humans, Biochemistry, Genetics and Molecular Biology(all), MESH: Alleles, Haplotype, MESH: Fertility, General Chemistry, Brain Disorders, MESH: Inbreeding Depression, 030104 developmental biology, Fertility, Haplotypes, Genetic markers, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Genetics and Molecular Biology(all)
Abstract: Publisher's version (útgefin grein)., In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding., This paper is the work of the ROHgen consortium. We thank the Sigma T2D Consortium, whose members are detailed in Supplementary Note 3. We thank the UK Biobank Resource, approved under application 19655; we acknowledge funding from the UK Medical Research Council Human Genetics Unit and MRC Doctoral Training Programme in Precision Medicine. We also thank Neil Robertson, Wellcome Trust Centre for Human Genetics, Oxford, for use of his author details management software, Authorial. Finally, we thank all the participants, researchers and funders of ROHgen cohorts. Cohort-specific acknowledgements are in Supplementary Data 2; personal acknowledgements and disclosures are in Supplementary Note 2. We thank Rachel Edwards for administrative assistance.
Published: 2019
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25. Integrating multiple lines of evidence to assess the effects of maternal BMI on pregnancy and perinatal outcomes.

Author: Borges MC, Clayton GL, Freathy RM, Felix JF, Fernández-Sanlés A, Soares AG, Kilpi F, Yang Q, McEachan RRC, Richmond RC, Liu X, Skotte L, Irizar A, Hattersley AT, Bodinier B, Scholtens DM, Nohr EA, Bond TA, Hayes MG, West J, Tyrrell J, Wright J, Bouchard L, Murcia M, Bustamante M, Chadeau-Hyam M, Jarvelin MR, Vrijheid M, Perron P, Magnus P, Gaillard R, Jaddoe VWV, Lowe WL Jr, Feenstra B, Hivert MF, Sørensen TIA, Håberg SE, Serbert S, Magnus M, and Lawlor DA
Subjects: Female, Humans, Infant, Newborn, Pregnancy, Body Mass Index, Cesarean Section, Mendelian Randomization Analysis, Diabetes, Gestational, Hypertension, Pregnancy-Induced epidemiology, Pre-Eclampsia epidemiology
Abstract: Background: Higher maternal pre-pregnancy body mass index (BMI) is associated with adverse pregnancy and perinatal outcomes. However, whether these associations are causal remains unclear., Methods: We explored the relation of maternal pre-/early-pregnancy BMI with 20 pregnancy and perinatal outcomes by integrating evidence from three different approaches (i.e. multivariable regression, Mendelian randomisation, and paternal negative control analyses), including data from over 400,000 women., Results: All three analytical approaches supported associations of higher maternal BMI with lower odds of maternal anaemia, delivering a small-for-gestational-age baby and initiating breastfeeding, but higher odds of hypertensive disorders of pregnancy, gestational hypertension, preeclampsia, gestational diabetes, pre-labour membrane rupture, induction of labour, caesarean section, large-for-gestational age, high birthweight, low Apgar score at 1 min, and neonatal intensive care unit admission. For example, higher maternal BMI was associated with higher risk of gestational hypertension in multivariable regression (OR = 1.67; 95% CI = 1.63, 1.70 per standard unit in BMI) and Mendelian randomisation (OR = 1.59; 95% CI = 1.38, 1.83), which was not seen for paternal BMI (OR = 1.01; 95% CI = 0.98, 1.04). Findings did not support a relation between maternal BMI and perinatal depression. For other outcomes, evidence was inconclusive due to inconsistencies across the applied approaches or substantial imprecision in effect estimates from Mendelian randomisation., Conclusions: Our findings support a causal role for maternal pre-/early-pregnancy BMI on 14 out of 20 adverse pregnancy and perinatal outcomes. Pre-conception interventions to support women maintaining a healthy BMI may reduce the burden of obstetric and neonatal complications., Funding: Medical Research Council, British Heart Foundation, European Research Council, National Institutes of Health, National Institute for Health Research, Research Council of Norway, Wellcome Trust., (© 2024. The Author(s).)
Published: 2024
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26. 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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27. Author Correction: Genetic effects on the timing of parturition and links to fetal birth weight.

Author: Solé-Navais P, Flatley C, Steinthorsdottir V, Vaudel M, Juodakis J, Chen J, Laisk T, LaBella AL, Westergaard D, Bacelis J, Brumpton B, Skotte L, Borges MC, Helgeland Ø, Mahajan A, Wielscher M, Lin F, Briggs C, Wang CA, Moen GH, Beaumont RN, Bradfield JP, Abraham A, Thorleifsson G, Gabrielsen ME, Ostrowski SR, Modzelewska D, Nohr EA, Hypponen E, Srivastava A, Talbot O, Allard C, Williams SM, Menon R, Shields BM, Sveinbjornsson G, Xu H, Melbye M, Lowe W Jr, Bouchard L, Oken E, Pedersen OB, Gudbjartsson DF, Erikstrup C, Sørensen E, Lie RT, Teramo K, Hallman M, Juliusdottir T, Hakonarson H, Ullum H, Hattersley AT, Sletner L, Merialdi M, Rifas-Shiman SL, Steingrimsdottir T, Scholtens D, Power C, West J, Nyegaard M, Capra JA, Skogholt AH, Magnus P, Andreassen OA, Thorsteinsdottir U, Grant SFA, Qvigstad E, Pennell CE, Hivert MF, Hayes GM, Jarvelin MR, McCarthy MI, Lawlor DA, Nielsen HS, Mägi R, Rokas A, Hveem K, Stefansson K, Feenstra B, Njolstad P, Muglia LJ, Freathy RM, Johansson S, Zhang G, and Jacobsson B
Published: 2023
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28. Genetic effects on the timing of parturition and links to fetal birth weight.

Author: Solé-Navais P, Flatley C, Steinthorsdottir V, Vaudel M, Juodakis J, Chen J, Laisk T, LaBella AL, Westergaard D, Bacelis J, Brumpton B, Skotte L, Borges MC, Helgeland Ø, Mahajan A, Wielscher M, Lin F, Briggs C, Wang CA, Moen GH, Beaumont RN, Bradfield JP, Abraham A, Thorleifsson G, Gabrielsen ME, Ostrowski SR, Modzelewska D, Nohr EA, Hypponen E, Srivastava A, Talbot O, Allard C, Williams SM, Menon R, Shields BM, Sveinbjornsson G, Xu H, Melbye M, Lowe W Jr, Bouchard L, Oken E, Pedersen OB, Gudbjartsson DF, Erikstrup C, Sørensen E, Lie RT, Teramo K, Hallman M, Juliusdottir T, Hakonarson H, Ullum H, Hattersley AT, Sletner L, Merialdi M, Rifas-Shiman SL, Steingrimsdottir T, Scholtens D, Power C, West J, Nyegaard M, Capra JA, Skogholt AH, Magnus P, Andreassen OA, Thorsteinsdottir U, Grant SFA, Qvigstad E, Pennell CE, Hivert MF, Hayes GM, Jarvelin MR, McCarthy MI, Lawlor DA, Nielsen HS, Mägi R, Rokas A, Hveem K, Stefansson K, Feenstra B, Njolstad P, Muglia LJ, Freathy RM, Johansson S, Zhang G, and Jacobsson B
Subjects: Pregnancy, Infant, Newborn, Female, Humans, Birth Weight genetics, Gestational Age, Parturition genetics, Premature Birth genetics
Abstract: The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n = 195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed six associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n = 136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal-fetal relationship between gestational duration and birth weight., (© 2023. The Author(s).)
Published: 2023
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29. An LDLR missense variant poses high risk of familial hypercholesterolemia in 30% of Greenlanders and offers potential of early cardiovascular disease intervention.

Author: Jørsboe E, Andersen MK, Skotte L, Stæger FF, Færgeman NJ, Hanghøj K, Santander CG, Senftleber NK, Diaz LJ, Overvad M, Waples RK, Geller F, Bjerregaard P, Melbye M, Larsen CVL, Feenstra B, Anders Koch, Jørgensen ME, Grarup N, Moltke I, Albrechtsen A, and Hansen T
Abstract: The common Arctic-specific LDLR p.G137S variant was recently shown to be associated with elevated lipid levels. Motivated by this, we aimed to investigate the effect of p.G137S on metabolic health and cardiovascular disease risk among Greenlanders to quantify its impact on the population. In a population-based Greenlandic cohort (n = 5,063), we tested for associations between the p.G137S variant and metabolic health traits as well as cardiovascular disease risk based on registry data. In addition, we explored the variant's impact on plasma NMR measured lipoprotein concentration and composition in another Greenlandic cohort (n = 1,629); 29.5% of the individuals in the cohort carried at least one copy of the p.G137S risk allele. Furthermore, 25.4% of the heterozygous and 54.7% of the homozygous carriers had high levels (>4.9 mmol/L) of serum LDL cholesterol, which is above the diagnostic level for familial hypercholesterolemia (FH). Moreover, p.G137S was associated with an overall atherosclerotic lipid profile, and increased risk of ischemic heart disease (HR [95% CI], 1.51 [1.18-1.92], p = 0.00096), peripheral artery disease (1.69 [1.01-2.82], p = 0.046), and coronary operations (1.78 [1.21-2.62], p = 0.0035). Due to its high frequency and large effect sizes, p.G137S has a marked population-level impact, increasing the risk of FH and cardiovascular disease for up to 30% of the Greenlandic population. Thus, p.G137S is a potential marker for early intervention in Arctic populations., Competing Interests: The authors declare no competing interests., (© 2022.)
Published: 2022
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30. Comprehensive genome-wide association study of different forms of hernia identifies more than 80 associated loci.

Author: Fadista J, Skotte L, Karjalainen J, Abner E, Sørensen E, Ullum H, Werge T, Esko T, Milani L, Palotie A, Daly M, Melbye M, Feenstra B, and Geller F
Subjects: Collagen metabolism, Follow-Up Studies, Genome-Wide Association Study, Humans, Hernia, Inguinal genetics, Hernia, Inguinal surgery
Abstract: Hernias are characterized by protrusion of an organ or tissue through its surrounding cavity and often require surgical repair. In this study we identify 65,492 cases for five hernia types in the UK Biobank and perform genome-wide association study scans for these five types and two combined groups. Our results show associated variants in all scans. Inguinal hernia has the most associations and we conduct a follow-up study with 23,803 additional cases from four study groups giving 84 independently associated variants. Identified variants from all scans are collapsed into 81 independent loci. Further testing shows that 26 loci are associated with more than one hernia type, suggesting substantial overlap between the underlying genetic mechanisms. Pathway analyses identify several genes with a strong link to collagen and/or elastin (ADAMTS6, ADAMTS16, ADAMTSL3, LOX, ELN) in the vicinity of associated loci for inguinal hernia, which substantiates an essential role of connective tissue morphology., (© 2022. The Author(s).)
Published: 2022
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31. Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes.

Author: Skotte L, Fadista J, Bybjerg-Grauholm J, Appadurai V, Hildebrand MS, Hansen TF, Banasik K, Grove J, Albiñana C, Geller F, Bjurström CF, Vilhjálmsson BJ, Coleman M, Damiano JA, Burgess R, Scheffer IE, Pedersen OBV, Erikstrup C, Westergaard D, Nielsen KR, Sørensen E, Bruun MT, Liu X, Hjalgrim H, Pers TH, Mortensen PB, Mors O, Nordentoft M, Dreier JW, Børglum AD, Christensen J, Hougaard DM, Buil A, Hviid A, Melbye M, Ullum H, Berkovic SF, Werge T, and Feenstra B
Subjects: Anoctamins genetics, Child, Child, Preschool, Fever complications, Fever genetics, Genome-Wide Association Study, Humans, NAV1.1 Voltage-Gated Sodium Channel genetics, Epilepsy genetics, Seizures, Febrile genetics
Abstract: Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy. We conducted a genome-wide association study of febrile seizures in 7635 cases and 83 966 controls identifying and replicating seven new loci, all with P < 5 × 10-10. Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10, and four other loci harboured genes (BSN, ERC2, GABRG2, HERC1) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. Four previously reported loci (SCN1A, SCN2A, ANO3 and 12q21.33) were all confirmed. Collectively, the seven novel and four previously reported loci explained 2.8% of the variance in liability to febrile seizures, and the single nucleotide polymorphism heritability based on all common autosomal single nucleotide polymorphisms was 10.8%. GABRG2, SCN1A and SCN2A are well-established epilepsy genes and, overall, we found positive genetic correlations with epilepsies (rg = 0.39, P = 1.68 × 10-4). Further, we found that higher polygenic risk scores for febrile seizures were associated with epilepsy and with history of hospital admission for febrile seizures. Finally, we found that polygenic risk of febrile seizures was lower in febrile seizure patients with neuropsychiatric disease compared to febrile seizure patients in a general population sample. In conclusion, this largest genetic investigation of febrile seizures to date implicates central fever response genes as well as genes affecting neuronal excitability, including several known epilepsy genes. Further functional and genetic studies based on these findings will provide important insights into the complex pathophysiological processes of seizures with and without fever., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)
Published: 2022
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32. Loss of Sucrase-Isomaltase Function Increases Acetate Levels and Improves Metabolic Health in Greenlandic Cohorts.

Author: Andersen MK, Skotte L, Jørsboe E, Polito R, Stæger FF, Aldiss P, Hanghøj K, Waples RK, Santander CG, Grarup N, Dahl-Petersen IK, Diaz LJ, Overvad M, Senftleber NK, Søborg B, Larsen CVL, Lemoine C, Pedersen O, Feenstra B, Bjerregaard P, Melbye M, Jørgensen ME, Færgeman NJ, Koch A, Moritz T, Gillum MP, Moltke I, Hansen T, and Albrechtsen A
Subjects: Acetates, Animals, Carbohydrate Metabolism, Inborn Errors, Humans, Mice, Oligo-1,6-Glucosidase, Dietary Sucrose adverse effects, Sucrase-Isomaltase Complex deficiency, Sucrase-Isomaltase Complex genetics, Sucrase-Isomaltase Complex metabolism
Abstract: Background & Aims: The sucrase-isomaltase (SI) c.273_274delAG loss-of-function variant is common in Arctic populations and causes congenital sucrase-isomaltase deficiency, which is an inability to break down and absorb sucrose and isomaltose. Children with this condition experience gastrointestinal symptoms when dietary sucrose is introduced. We aimed to describe the health of adults with sucrase-isomaltase deficiency., Methods: The association between c.273_274delAG and phenotypes related to metabolic health was assessed in 2 cohorts of Greenlandic adults (n = 4922 and n = 1629). A sucrase-isomaltase knockout (Sis-KO) mouse model was used to further elucidate the findings., Results: Homozygous carriers of the variant had a markedly healthier metabolic profile than the remaining population, including lower body mass index (β [standard error], -2.0 [0.5] kg/m 2 ; P = 3.1 × 10 -5 ), body weight (-4.8 [1.4] kg; P = 5.1 × 10 -4 ), fat percentage (-3.3% [1.0%]; P = 3.7 × 10 -4 ), fasting triglyceride (-0.27 [0.07] mmol/L; P = 2.3 × 10 -6 ), and remnant cholesterol (-0.11 [0.03] mmol/L; P = 4.2 × 10 -5 ). Further analyses suggested that this was likely mediated partly by higher circulating levels of acetate observed in homozygous carriers (β [standard error], 0.056 [0.002] mmol/L; P = 2.1 × 10 -26 ), and partly by reduced sucrose uptake, but not lower caloric intake. These findings were verified in Sis-KO mice, which, compared with wild-type mice, were leaner on a sucrose-containing diet, despite similar caloric intake, had significantly higher plasma acetate levels in response to a sucrose gavage, and had lower plasma glucose level in response to a sucrose-tolerance test., Conclusions: These results suggest that sucrase-isomaltase constitutes a promising drug target for improvement of metabolic health, and that the health benefits are mediated by reduced dietary sucrose uptake and possibly also by higher levels of circulating acetate., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2022
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33. Seasonal Variation and Risk of Febrile Seizures: A Danish Nationwide Cohort Study.

Author: Christensen KJ, Dreier JW, Skotte L, Feenstra B, Grove J, Børglum AD, Mitrovic M, Cotsapas C, and Christensen J
Subjects: Child, Cohort Studies, Denmark epidemiology, Humans, Incidence, Infant, Seasons, Seizures, Febrile epidemiology, Seizures, Febrile etiology
Abstract: Introduction: Onset of febrile seizures varies with calendar season. However, it has not previously been assessed, how season of birth interacts with age and peak risk of febrile seizures, and whether season of birth correlates with the cumulative risk of febrile seizures at 5 years of age (i.e., when children are no longer of risk of febrile seizures)., Methods: We identified all singleton children born in Denmark between 1977 and 2011 who were alive at 3 months of age (N = 2,103,232). We used the Danish Civil Registration System to identify age and sex of the children and the Danish National Patient Register to identify children hospitalized with febrile seizures from 3 months to 5 years of age. Follow-up ended on December 31, 2016, when all children had reached 5 years of age., Results: The relative risk of admission with a first febrile seizure varied with calendar month; in February (a winter month in Denmark), the risk was more than doubled (hazard ratio: 2.10 [95% confidence interval [CI]: 2.03-2.18]) compared with August (a summer month in Denmark). The age-specific incidence of a first febrile seizure by birth month identified the highest peak incidence of a first febrile seizure among children born in November (reaching a peak incidence of 350 first admissions with a febrile seizure per 100,000 person months at age 16 months) as compared to children born in July (reaching a peak incidence of 200 first admissions with a febrile seizure per 100,000 person months at age 16 months). However, the cumulative incidence of any admission with febrile seizures before 5 years was not correlated with season of birth (3.69% [95% CI: 3.64-3.74%] for winter births, 3.57% [95% CI: 3.52-3.62%] for spring births, 3.55% [95% CI: 3.50-3.59%] for summer births, and 3.64% [95% CI: 3.59-3.69%] for fall births)., Discussion/conclusion: The study found a significant seasonal variation in onset of the first febrile seizure and in the age-specific peak incidence of febrile seizures. However, there was no correlation between season of birth and cumulative incidence of febrile seizures at 5 years of age suggesting that children who are predisposed to febrile seizures will eventually go on to experience a febrile seizure regardless of season of birth., (© 2022 S. Karger AG, Basel.)
Published: 2022
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34. Genetic regulation of spermine oxidase activity and cancer risk: a Mendelian randomization study.

Author: Fadista J, Yakimov V, Võsa U, Hansen CS, Kasela S, Skotte L, Geller F, Courraud J, Esko T, Kukuškina V, Buil A, Melbye M, Werge TM, Hougaard DM, Milani L, Bybjerg-Grauholm J, Cohen AS, and Feenstra B
Subjects: Adult, Gene Expression Regulation, Neoplastic, Humans, Infant, Newborn, Neoplasms etiology, Neoplasms metabolism, Phenotype, Polyamine Oxidase, Gene Expression Regulation, Enzymologic, Genetic Predisposition to Disease, Mendelian Randomization Analysis methods, Neoplasms pathology, Oxidoreductases Acting on CH-NH Group Donors genetics, Polymorphism, Single Nucleotide, Quantitative Trait Loci
Abstract: Spermine oxidase (SMOX) catalyzes the oxidation of spermine to spermidine. Observational studies have reported SMOX as a source of reactive oxygen species associated with cancer, implying that inhibition of SMOX could be a target for chemoprevention. Here we test causality of SMOX levels with cancer risk using a Mendelian randomization analysis. We performed a GWAS of spermidine/spermine ratio to identify genetic variants associated with regulation of SMOX activity. Replication analysis was performed in two datasets of SMOX gene expression. We then did a Mendelian randomization analysis by testing the association between the SMOX genetic instrument and neuroblastoma, gastric, lung, breast, prostate, and colorectal cancers using GWAS summary statistics. GWAS of spermidine/spermine ratio identified SMOX locus (P = 1.34 × 10 -49 ) explaining 32% of the variance. The lead SNP rs1741315 was also associated with SMOX gene expression in newborns (P = 8.48 × 10 -28 ) and adults (P = 2.748 × 10 -8 ) explaining 37% and 6% of the variance, respectively. Genetically determined SMOX activity was not associated with neuroblastoma, gastric, lung, breast, prostate nor colorectal cancer (P > 0.05). A PheWAS of rs1741315 did not reveal any relevant associations. Common genetic variation in the SMOX gene was strongly associated with SMOX activity in newborns, and less strongly in adults. Genetic down-regulation of SMOX was not significantly associated with lower odds of neuroblastoma, gastric, lung, breast, prostate and colorectal cancer. These results may inform studies of SMOX inhibition as a target for chemoprevention., (© 2021. The Author(s).)
Published: 2021
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35. Birth characteristics and risk of febrile seizures.

Author: Christensen KJ, Dreier JW, Skotte L, Feenstra B, Grove J, Børglum A, Mitrovic M, Cotsapas C, and Christensen J
Subjects: Child, Preschool, Cohort Studies, Denmark epidemiology, Follow-Up Studies, Humans, Infant, Infant, Newborn, Male, Registries, Risk Factors, Seizures, Febrile physiopathology, Sex Factors, Birth Weight physiology, Child Development physiology, Gestational Age, Seizures, Febrile diagnosis, Seizures, Febrile epidemiology
Abstract: Objective: Febrile seizure is a common childhood disorder that affects 2-5% of all children, and is associated with later development of epilepsy and psychiatric disorders. This study determines how the incidence of febrile seizures correlates with birth characteristics, age, sex and brain development., Methods: This is a cohort study of all children born Denmark between 1977 and 2011 who were alive at 3 months of age (N = 2,103,232). The Danish National Patient Register was used to identify children with febrile seizures up to 5 years of age. Follow-up ended on 31 December 2016 when all cohort members had potentially reached 5 years of age., Results: In total, 75,593 (3.59%, 95% CI: 3.57-3.62%) were diagnosed with febrile seizures. Incidence peaked at 16.7 months of age (median: 16.7 months, interquartile range: 12.5-24.0). The 5-year cumulative incidence of febrile seizures increased with decreasing birth weight (<1500 g; 5.42% (95% CI: 4.98-5.88% vs. 3,000-4,000 g; 3.53% (95% CI: 3.50-3.56%)) and with decreasing gestational age at birth (31-32 weeks; 5.90% (95% CI: 5.40-6.44%) vs. 39-40 weeks; 3.56% (95% CI: 3.53-3.60)). Lower gestational age at birth was associated with higher age at onset of a first febrile seizure; an association that essentially disappeared when correcting for age from conception., Conclusions: The risk of febrile seizures increased with decreasing birth weight and gestational age at birth. The association between low gestational age at birth and age at first febrile seizure suggests that onset of febrile seizures is associated with the stage of brain development., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
Published: 2021
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36. Integrating genetics with newborn metabolomics in infantile hypertrophic pyloric stenosis.

Author: Fadista J, Skotte L, Courraud J, Geller F, Gørtz S, Wohlfahrt J, Melbye M, Cohen AS, and Feenstra B
Subjects: Case-Control Studies, Chromatography, Liquid, Computational Biology, Denmark, Feeding Behavior, Female, Genetic Association Studies, Genetic Variation, Humans, Infant, Newborn, Male, Mass Spectrometry, Polymorphism, Single Nucleotide, Pyloric Stenosis, Hypertrophic diagnosis, Biomarkers, Genetic Predisposition to Disease, Metabolome, Metabolomics methods, Pyloric Stenosis, Hypertrophic genetics, Pyloric Stenosis, Hypertrophic metabolism
Abstract: Introduction: Infantile hypertrophic pyloric stenosis (IHPS) is caused by hypertrophy of the pyloric sphincter muscle., Objectives: Since previous reports have implicated lipid metabolism, we aimed to (1) investigate associations between IHPS and a wide array of lipid-related metabolites in newborns, and (2) address whether detected differences in metabolite levels were likely to be driven by genetic differences between IHPS cases and controls or by differences in early life feeding patterns., Methods: We used population-based random selection of IHPS cases and controls born in Denmark between 1997 and 2014. We randomly took dried blood spots of newborns from 267 pairs of IHPS cases and controls matched by sex and day of birth. We used a mixed-effects linear regression model to evaluate associations between 148 metabolites and IHPS in a matched case-control design., Results: The phosphatidylcholine PC(38:4) showed significantly lower levels in IHPS cases (P = 4.68 × 10 -8 ) as did six other correlated metabolites (four phosphatidylcholines, acylcarnitine AC(2:0), and histidine). Associations were driven by 98 case-control pairs born before 2009, when median age at sampling was 6 days. No association was seen in 169 pairs born in 2009 or later, when median age at sampling was 2 days. More IHPS cases than controls had a diagnosis for neonatal difficulty in feeding at breast (P = 6.15 × 10 -3 ). Genetic variants known to be associated with PC(38:4) levels did not associate with IHPS., Conclusions: We detected lower levels of certain metabolites in IHPS, possibly reflecting different feeding patterns in the first days of life.
Published: 2021
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37. Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women.

Author: Steinthorsdottir V, McGinnis R, Williams NO, Stefansdottir L, Thorleifsson G, Shooter S, Fadista J, Sigurdsson JK, Auro KM, Berezina G, Borges MC, Bumpstead S, Bybjerg-Grauholm J, Colgiu I, Dolby VA, Dudbridge F, Engel SM, Franklin CS, Frigge ML, Frisbaek Y, Geirsson RT, Geller F, Gretarsdottir S, Gudbjartsson DF, Harmon Q, Hougaard DM, Hegay T, Helgadottir A, Hjartardottir S, Jääskeläinen T, Johannsdottir H, Jonsdottir I, Juliusdottir T, Kalsheker N, Kasimov A, Kemp JP, Kivinen K, Klungsøyr K, Lee WK, Melbye M, Miedzybrodska Z, Moffett A, Najmutdinova D, Nishanova F, Olafsdottir T, Perola M, Pipkin FB, Poston L, Prescott G, Saevarsdottir S, Salimbayeva D, Scaife PJ, Skotte L, Staines-Urias E, Stefansson OA, Sørensen KM, Thomsen LCV, Tragante V, Trogstad L, Simpson NAB, Aripova T, Casas JP, Dominiczak AF, Walker JJ, Thorsteinsdottir U, Iversen AC, Feenstra B, Lawlor DA, Boyd HA, Magnus P, Laivuori H, Zakhidova N, Svyatova G, Stefansson K, and Morgan L
Subjects: Adaptor Proteins, Signal Transducing genetics, Adult, Aged, Alpha-Ketoglutarate-Dependent Dioxygenase FTO genetics, Asia, Central epidemiology, Blood Pressure genetics, Case-Control Studies, Datasets as Topic, Europe epidemiology, Female, Fibroblast Growth Factor 5 genetics, Genetic Loci genetics, Genome-Wide Association Study, Humans, Hypertension, Pregnancy-Induced epidemiology, MDS1 and EVI1 Complex Locus Protein genetics, Middle Aged, Pre-Eclampsia epidemiology, Pregnancy, Prospective Studies, Genetic Predisposition to Disease, Hypertension, Pregnancy-Induced genetics, Multifactorial Inheritance, Pre-Eclampsia genetics
Abstract: Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.
Published: 2020
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38. Genome-wide Study Identifies Association between HLA-B ∗ 55:01 and Self-Reported Penicillin Allergy.

Author: Krebs K, Bovijn J, Zheng N, Lepamets M, Censin JC, Jürgenson T, Särg D, Abner E, Laisk T, Luo Y, Skotte L, Geller F, Feenstra B, Wang W, Auton A, Raychaudhuri S, Esko T, Metspalu A, Laur S, Roden DM, Wei WQ, Holmes MV, Lindgren CM, Phillips EJ, Mägi R, Milani L, and Fadista J
Subjects: Adult, Alleles, Arthritis, Rheumatoid complications, Arthritis, Rheumatoid immunology, Chromosomes, Human, Pair 6 chemistry, Drug Hypersensitivity complications, Drug Hypersensitivity etiology, Drug Hypersensitivity immunology, Electronic Health Records, Europe, Female, Gene Expression, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, HLA-B Antigens immunology, Histocompatibility Testing, Humans, Male, Penicillins adverse effects, Protein Tyrosine Phosphatase, Non-Receptor Type 22 immunology, Psoriasis complications, Psoriasis immunology, Self Report, T-Lymphocytes immunology, T-Lymphocytes pathology, United States, Arthritis, Rheumatoid genetics, Drug Hypersensitivity genetics, HLA-B Antigens genetics, Polymorphism, Single Nucleotide, Protein Tyrosine Phosphatase, Non-Receptor Type 22 genetics, Psoriasis genetics
Abstract: Hypersensitivity reactions to drugs are often unpredictable and can be life threatening, underscoring a need for understanding their underlying mechanisms and risk factors. The extent to which germline genetic variation influences the risk of commonly reported drug allergies such as penicillin allergy remains largely unknown. We extracted data from the electronic health records of more than 600,000 participants from the UK, Estonian, and Vanderbilt University Medical Center's BioVU biobanks to study the role of genetic variation in the occurrence of self-reported penicillin hypersensitivity reactions. We used imputed SNP to HLA typing data from these cohorts to further fine map the human leukocyte antigen (HLA) association and replicated our results in 23andMe's research cohort involving a total of 1.12 million individuals. Genome-wide meta-analysis of penicillin allergy revealed two loci, including one located in the HLA region on chromosome 6. This signal was further fine-mapped to the HLA-B ∗ 55:01 allele (OR 1.41 95% CI 1.33-1.49, p value 2.04 × 10 -31 ) and confirmed by independent replication in 23andMe's research cohort (OR 1.30 95% CI 1.25-1.34, p value 1.00 × 10 -47 ). The lead SNP was also associated with lower lymphocyte counts and in silico follow-up suggests a potential effect on T-lymphocytes at HLA-B ∗ 55:01. We also observed a significant hit in PTPN22 and the GWAS results correlated with the genetics of rheumatoid arthritis and psoriasis. We present robust evidence for the role of an allele of the major histocompatibility complex (MHC) I gene HLA-B in the occurrence of penicillin allergy., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
Published: 2020
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39. Metabolic Dynamics and Prediction of Gestational Age and Time to Delivery in Pregnant Women.

Author: Liang L, Rasmussen MH, Piening B, Shen X, Chen S, Röst H, Snyder JK, Tibshirani R, Skotte L, Lee NC, Contrepois K, Feenstra B, Zackriah H, Snyder M, and Melbye M
Subjects: Adult, Biomarkers blood, Female, Fetus metabolism, Humans, Metabolic Networks and Pathways physiology, Metabolome physiology, Pregnant People, Gestational Age, Metabolomics methods, Pregnancy metabolism
Abstract: Metabolism during pregnancy is a dynamic and precisely programmed process, the failure of which can bring devastating consequences to the mother and fetus. To define a high-resolution temporal profile of metabolites during healthy pregnancy, we analyzed the untargeted metabolome of 784 weekly blood samples from 30 pregnant women. Broad changes and a highly choreographed profile were revealed: 4,995 metabolic features (of 9,651 total), 460 annotated compounds (of 687 total), and 34 human metabolic pathways (of 48 total) were significantly changed during pregnancy. Using linear models, we built a metabolic clock with five metabolites that time gestational age in high accordance with ultrasound (R = 0.92). Furthermore, two to three metabolites can identify when labor occurs (time to delivery within two, four, and eight weeks, AUROC ≥ 0.85). Our study represents a weekly characterization of the human pregnancy metabolome, providing a high-resolution landscape for understanding pregnancy with potential clinical utilities., Competing Interests: Declaration of Interests M.S. is a co-founder and member of the scientific advisory boards of the following: Personalis, SensOmics, Filtricine, Qbio, January, Mirvie, and Oralome. He is a member of the scientific advisory board of Jungla. M.M. is a co-founder of Mirvie. L.L., M.S., and M.M. are inventors on the patent application PCT/US2019/052515 related to this work., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2020
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40. The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders.

Author: Andersen MK, Jørsboe E, Skotte L, Hanghøj K, Sandholt CH, Moltke I, Grarup N, Kern T, Mahendran Y, Søborg B, Bjerregaard P, Larsen CVL, Dahl-Petersen IK, Tiwari HK, Feenstra B, Koch A, Wiener HW, Hopkins SE, Pedersen O, Melbye M, Boyer BB, Jørgensen ME, Albrechtsen A, and Hansen T
Subjects: Adiposity, Cholesterol blood, DNA, Intergenic genetics, Female, Greenland, Humans, Insulin Resistance, Male, Metabolome, Waist Circumference, Body Mass Index, Chromosomes, Human, Pair 11 genetics, Inuit genetics, Polymorphism, Single Nucleotide
Abstract: The genetic architecture of the small and isolated Greenlandic population is advantageous for identification of novel genetic variants associated with cardio-metabolic traits. We aimed to identify genetic loci associated with body mass index (BMI), to expand the knowledge of the genetic and biological mechanisms underlying obesity. Stage 1 BMI-association analyses were performed in 4,626 Greenlanders. Stage 2 replication and meta-analysis were performed in additional cohorts comprising 1,058 Yup'ik Alaska Native people, and 1,529 Greenlanders. Obesity-related traits were assessed in the stage 1 study population. We identified a common variant on chromosome 11, rs4936356, where the derived G-allele had a frequency of 24% in the stage 1 study population. The derived allele was genome-wide significantly associated with lower BMI (beta (SE), -0.14 SD (0.03), p = 3.2x10-8), corresponding to 0.64 kg/m2 lower BMI per G allele in the stage 1 study population. We observed a similar effect in the Yup'ik cohort (-0.09 SD, p = 0.038), and a non-significant effect in the same direction in the independent Greenlandic stage 2 cohort (-0.03 SD, p = 0.514). The association remained genome-wide significant in meta-analysis of the Arctic cohorts (-0.10 SD (0.02), p = 4.7x10-8). Moreover, the variant was associated with a leaner body type (weight, -1.68 (0.37) kg; waist circumference, -1.52 (0.33) cm; hip circumference, -0.85 (0.24) cm; lean mass, -0.84 (0.19) kg; fat mass and percent, -1.66 (0.33) kg and -1.39 (0.27) %; visceral adipose tissue, -0.30 (0.07) cm; subcutaneous adipose tissue, -0.16 (0.05) cm, all p<0.0002), lower insulin resistance (HOMA-IR, -0.12 (0.04), p = 0.00021), and favorable lipid levels (triglyceride, -0.05 (0.02) mmol/l, p = 0.025; HDL-cholesterol, 0.04 (0.01) mmol/l, p = 0.0015). In conclusion, we identified a novel variant, where the derived G-allele possibly associated with lower BMI in Arctic populations, and as a consequence also leaner body type, lower insulin resistance, and a favorable lipid profile., Competing Interests: The authors have declared that no competing interests exist.
Published: 2020
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41. Associations of autozygosity with a broad range of human phenotypes.

Author: Clark DW, Okada Y, Moore KHS, Mason D, Pirastu N, Gandin I, Mattsson H, Barnes CLK, Lin K, Zhao JH, Deelen P, Rohde R, Schurmann C, Guo X, Giulianini F, Zhang W, Medina-Gomez C, Karlsson R, Bao Y, Bartz TM, Baumbach C, Biino G, Bixley MJ, Brumat M, Chai JF, Corre T, Cousminer DL, Dekker AM, Eccles DA, van Eijk KR, Fuchsberger C, Gao H, Germain M, Gordon SD, de Haan HG, Harris SE, Hofer E, Huerta-Chagoya A, Igartua C, Jansen IE, Jia Y, Kacprowski T, Karlsson T, Kleber ME, Li SA, Li-Gao R, Mahajan A, Matsuda K, Meidtner K, Meng W, Montasser ME, van der Most PJ, Munz M, Nutile T, Palviainen T, Prasad G, Prasad RB, Priyanka TDS, Rizzi F, Salvi E, Sapkota BR, Shriner D, Skotte L, Smart MC, Smith AV, van der Spek A, Spracklen CN, Strawbridge RJ, Tajuddin SM, Trompet S, Turman C, Verweij N, Viberti C, Wang L, Warren HR, Wootton RE, Yanek LR, Yao J, Yousri NA, Zhao W, Adeyemo AA, Afaq S, Aguilar-Salinas CA, Akiyama M, Albert ML, Allison MA, Alver M, Aung T, Azizi F, Bentley AR, Boeing H, Boerwinkle E, Borja JB, de Borst GJ, Bottinger EP, Broer L, Campbell H, Chanock S, Chee ML, Chen G, Chen YI, Chen Z, Chiu YF, Cocca M, Collins FS, Concas MP, Corley J, Cugliari G, van Dam RM, Damulina A, Daneshpour MS, Day FR, Delgado GE, Dhana K, Doney ASF, Dörr M, Doumatey AP, Dzimiri N, Ebenesersdóttir SS, Elliott J, Elliott P, Ewert R, Felix JF, Fischer K, Freedman BI, Girotto G, Goel A, Gögele M, Goodarzi MO, Graff M, Granot-Hershkovitz E, Grodstein F, Guarrera S, Gudbjartsson DF, Guity K, Gunnarsson B, Guo Y, Hagenaars SP, Haiman CA, Halevy A, Harris TB, Hedayati M, van Heel DA, Hirata M, Höfer I, Hsiung CA, Huang J, Hung YJ, Ikram MA, Jagadeesan A, Jousilahti P, Kamatani Y, Kanai M, Kerrison ND, Kessler T, Khaw KT, Khor CC, de Kleijn DPV, Koh WP, Kolcic I, Kraft P, Krämer BK, Kutalik Z, Kuusisto J, Langenberg C, Launer LJ, Lawlor DA, Lee IT, Lee WJ, Lerch MM, Li L, Liu J, Loh M, London SJ, Loomis S, Lu Y, Luan J, Mägi R, Manichaikul AW, Manunta P, Másson G, Matoba N, Mei XW, Meisinger C, Meitinger T, Mezzavilla M, Milani L, Millwood IY, Momozawa Y, Moore A, Morange PE, Moreno-Macías H, Mori TA, Morrison AC, Muka T, Murakami Y, Murray AD, de Mutsert R, Mychaleckyj JC, Nalls MA, Nauck M, Neville MJ, Nolte IM, Ong KK, Orozco L, Padmanabhan S, Pálsson G, Pankow JS, Pattaro C, Pattie A, Polasek O, Poulter N, Pramstaller PP, Quintana-Murci L, Räikkönen K, Ralhan S, Rao DC, van Rheenen W, Rich SS, Ridker PM, Rietveld CA, Robino A, van Rooij FJA, Ruggiero D, Saba Y, Sabanayagam C, Sabater-Lleal M, Sala CF, Salomaa V, Sandow K, Schmidt H, Scott LJ, Scott WR, Sedaghati-Khayat B, Sennblad B, van Setten J, Sever PJ, Sheu WH, Shi Y, Shrestha S, Shukla SR, Sigurdsson JK, Sikka TT, Singh JR, Smith BH, Stančáková A, Stanton A, Starr JM, Stefansdottir L, Straker L, Sulem P, Sveinbjornsson G, Swertz MA, Taylor AM, Taylor KD, Terzikhan N, Tham YC, Thorleifsson G, Thorsteinsdottir U, Tillander A, Tracy RP, Tusié-Luna T, Tzoulaki I, Vaccargiu S, Vangipurapu J, Veldink JH, Vitart V, Völker U, Vuoksimaa E, Wakil SM, Waldenberger M, Wander GS, Wang YX, Wareham NJ, Wild S, Yajnik CS, Yuan JM, Zeng L, Zhang L, Zhou J, Amin N, Asselbergs FW, Bakker SJL, Becker DM, Lehne B, Bennett DA, van den Berg LH, Berndt SI, Bharadwaj D, Bielak LF, Bochud M, Boehnke M, Bouchard C, Bradfield JP, Brody JA, Campbell A, Carmi S, Caulfield MJ, Cesarini D, Chambers JC, Chandak GR, Cheng CY, Ciullo M, Cornelis M, Cusi D, Smith GD, Deary IJ, Dorajoo R, van Duijn CM, Ellinghaus D, Erdmann J, Eriksson JG, Evangelou E, Evans MK, Faul JD, Feenstra B, Feitosa M, Foisy S, Franke A, Friedlander Y, Gasparini P, Gieger C, Gonzalez C, Goyette P, Grant SFA, Griffiths LR, Groop L, Gudnason V, Gyllensten U, Hakonarson H, Hamsten A, van der Harst P, Heng CK, Hicks AA, Hochner H, Huikuri H, Hunt SC, Jaddoe VWV, De Jager PL, Johannesson M, Johansson Å, Jonas JB, Jukema JW, Junttila J, Kaprio J, Kardia SLR, Karpe F, Kumari M, Laakso M, van der Laan SW, Lahti J, Laudes M, Lea RA, Lieb W, Lumley T, Martin NG, März W, Matullo G, McCarthy MI, Medland SE, Merriman TR, Metspalu A, Meyer BF, Mohlke KL, Montgomery GW, Mook-Kanamori D, Munroe PB, North KE, Nyholt DR, O'connell JR, Ober C, Oldehinkel AJ, Palmas W, Palmer C, Pasterkamp GG, Patin E, Pennell CE, Perusse L, Peyser PA, Pirastu M, Polderman TJC, Porteous DJ, Posthuma D, Psaty BM, Rioux JD, Rivadeneira F, Rotimi C, Rotter JI, Rudan I, Den Ruijter HM, Sanghera DK, Sattar N, Schmidt R, Schulze MB, Schunkert H, Scott RA, Shuldiner AR, Sim X, Small N, Smith JA, Sotoodehnia N, Tai ES, Teumer A, Timpson NJ, Toniolo D, Tregouet DA, Tuomi T, Vollenweider P, Wang CA, Weir DR, Whitfield JB, Wijmenga C, Wong TY, Wright J, Yang J, Yu L, Zemel BS, Zonderman AB, Perola M, Magnusson PKE, Uitterlinden AG, Kooner JS, Chasman DI, Loos RJF, Franceschini N, Franke L, Haley CS, Hayward C, Walters RG, Perry JRB, Esko T, Helgason A, Stefansson K, Joshi PK, Kubo M, and Wilson JF
Subjects: Alleles, Haplotypes, Homozygote, Humans, Body Size genetics, Cognition, Consanguinity, Fertility genetics, Health Status, Inbreeding Depression genetics, Risk-Taking
Abstract: In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F ROH ) for >1.4 million individuals, we show that F ROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F ROH are confirmed within full-sibling pairs, where the variation in F ROH is independent of all environmental confounding.
Published: 2019
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42. Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration.

Author: Liu X, Helenius D, Skotte L, Beaumont RN, Wielscher M, Geller F, Juodakis J, Mahajan A, Bradfield JP, Lin FTJ, Vogelezang S, Bustamante M, Ahluwalia TS, Pitkänen N, Wang CA, Bacelis J, Borges MC, Zhang G, Bedell BA, Rossi RM, Skogstrand K, Peng S, Thompson WK, Appadurai V, Lawlor DA, Kalliala I, Power C, McCarthy MI, Boyd HA, Marazita ML, Hakonarson H, Hayes MG, Scholtens DM, Rivadeneira F, Jaddoe VWV, Vinding RK, Bisgaard H, Knight BA, Pahkala K, Raitakari O, Helgeland Ø, Johansson S, Njølstad PR, Fadista J, Schork AJ, Nudel R, Miller DE, Chen X, Weirauch MT, Mortensen PB, Børglum AD, Nordentoft M, Mors O, Hao K, Ryckman KK, Hougaard DM, Kottyan LC, Pennell CE, Lyytikainen LP, Bønnelykke K, Vrijheid M, Felix JF, Lowe WL Jr, Grant SFA, Hyppönen E, Jacobsson B, Jarvelin MR, Muglia LJ, Murray JC, Freathy RM, Werge TM, Melbye M, Buil A, and Feenstra B
Subjects: Female, Genome-Wide Association Study, Gestational Age, Humans, Infant, Newborn, Pregnancy, Premature Birth genetics, Chromosomes, Human, Pair 2 genetics, Cytokines genetics, Fetus metabolism, Genome, Human genetics, Polymorphism, Single Nucleotide
Abstract: The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10 -14 ). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.
Published: 2019
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43. Ancestry-specific association mapping in admixed populations.

Author: Skotte L, Jørsboe E, Korneliussen TS, Moltke I, and Albrechtsen A
Subjects: Alleles, Case-Control Studies, Cohort Studies, Computer Simulation, Greenland, Humans, Models, Genetic, Phenotype, Polymorphism, Single Nucleotide genetics, Quantitative Trait Loci genetics, Genetics, Population, Genome-Wide Association Study, Phylogeny
Abstract: During the last decade genome-wide association studies have proven to be a powerful approach to identifying disease-causing variants. However, for admixed populations, most current methods for association testing are based on the assumption that the effect of a genetic variant is the same regardless of its ancestry. This is a reasonable assumption for a causal variant but may not hold for the genetic variants that are tested in genome-wide association studies, which are usually not causal. The effects of noncausal genetic variants depend on how strongly their presence correlate with the presence of the causal variant, which may vary between ancestral populations because of different linkage disequilibrium patterns and allele frequencies. Motivated by this, we here introduce a new statistical method for association testing in recently admixed populations, where the effect size is allowed to depend on the ancestry of a given allele. Our method does not rely on accurate inference of local ancestry, yet using simulations we show that in some scenarios it gives a substantial increase in statistical power to detect associations. In addition, the method allows for testing for difference in effect size between ancestral populations, which can be used to help determine if a given genetic variant is causal. We demonstrate the usefulness of the method on data from the Greenlandic population., (© 2019 Wiley Periodicals, Inc.)
Published: 2019
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44. Genome-wide meta-analysis identifies BARX1 and EML4-MTA3 as new loci associated with infantile hypertrophic pyloric stenosis.

Author: Fadista J, Skotte L, Geller F, Bybjerg-Grauholm J, Gørtz S, Romitti PA, Caggana M, Kay DM, Matsson H, Boyd HA, Hougaard DM, Nordenskjöld A, Mills JL, Melbye M, and Feenstra B
Subjects: Case-Control Studies, Cohort Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Infant, Infant, Newborn, Polymorphism, Single Nucleotide, Cell Cycle Proteins genetics, Homeodomain Proteins genetics, Microtubule-Associated Proteins genetics, Neoplasm Proteins genetics, Pyloric Stenosis, Hypertrophic genetics, Serine Endopeptidases genetics, Transcription Factors genetics
Abstract: Infantile hypertrophic pyloric stenosis (IHPS) is a disorder of young infants with a population incidence of ∼2/1000 live births, caused by hypertrophy of the pyloric sphincter smooth muscle. Reported genetic loci associated with IHPS explain only a minor proportion of IHPS risk. To identify new risk loci, we carried out a genome-wide meta-analysis on 1395 surgery-confirmed cases and 4438 controls, with replication in a set of 2427 cases and 2524 controls. We identified and replicated six independent genomic loci associated with IHPS risk at genome wide significance (P < 5 × 10-8), including novel associations with two single nucleotide polymorphisms (SNPs). One of these SNPs, rs6736913 [odds ratio (OR) = 2.32; P = 3.0 × 10-15], is a low frequency missense variant in EML4 at 2p21. The second SNP, rs1933683 (OR = 1.34; P = 3.1 × 10-9) is 1 kb downstream of BARX1 at 9q22.32, an essential gene for stomach formation in embryogenesis. Using the genome-wide complex trait analysis method, we estimated the IHPS SNP heritability to be 30%, and using the linkage disequilibrium score regression method, we found support for a previously reported genetic correlation of IHPS with lipid metabolism. By combining the largest collection of IHPS cases to date (3822 cases), with results generalized across populations of different ancestry, we elucidate novel mechanistic avenues of IHPS disease architecture.
Published: 2019
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45. Study of correlation between the NAT2 phenotype and genotype status among Greenlandic Inuit.

Author: Birch Kristensen E, Yakimov V, Bjorn-Mortensen K, Soborg B, Koch A, Andersson M, Birch Kristensen K, Michelsen SW, Skotte L, Ahrendt Bjerregaard A, Blaszkewicz M, Golka K, Hengstler JG, Feenstra B, Melbye M, and Geller F
Abstract: N -acetyltransferase 2 (NAT2) is the main enzyme metabolizing isoniazid and genotype-based treatment has been studied for years without becoming common practice. To investigate whether genotype-based isoniazid treatment is feasible in Greenland, we sequenced the coding sequence of NAT2 and determined the NAT2 enzyme-activity by caffeine test. No additional genetic variants were identified in the coding sequence of NAT2 , so that genotype status in 260 study participants could be assessed by a well-established 7-SNP panel. Studying the enzyme activity by the ratio of the two caffeine metabolites AFMU and 1X in 260 participants showed a high rate of slow phenotypes with intermediate or rapid genotype. These misclassifications were mainly observed in urine samples with pH<3, a deviation from the standard protocol due to the field work character of the study, where immediate pH adjustment to pH=3.5 was not possible. We excluded these samples. For the remaining 143 individuals with pH>3, we observed a moderate level of discrepancies (19 of the 116 individuals with intermediate or rapid genotype status having a slow phenotype). Further investigation showed that drinking coffee and not tea or cola was the most important factor for high levels of both metabolites. The concordance between phenotype and genotype status with regard to slow metabolism supported the recommendation of lower isoniazid doses in individuals with slow genotype status in order to avoid liver injury, a frequent side effect. The phenotypical variation observed for individuals with intermediate or rapid genotype status warrants further research before increased dosing of isoniazid can be recommended.
Published: 2018
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46. Noninvasive blood tests for fetal development predict gestational age and preterm delivery.

Author: Ngo TTM, Moufarrej MN, Rasmussen MH, Camunas-Soler J, Pan W, Okamoto J, Neff NF, Liu K, Wong RJ, Downes K, Tibshirani R, Shaw GM, Skotte L, Stevenson DK, Biggio JR, Elovitz MA, Melbye M, and Quake SR
Subjects: Adult, Female, Humans, Pilot Projects, Pregnancy, Prenatal Care, Young Adult, Blood Chemical Analysis methods, Cell-Free Nucleic Acids blood, Fetal Development, Fetal Monitoring methods, Gestational Age, Premature Birth blood, Premature Birth diagnosis
Abstract: Noninvasive blood tests that provide information about fetal development and gestational age could potentially improve prenatal care. Ultrasound, the current gold standard, is not always affordable in low-resource settings and does not predict spontaneous preterm birth, a leading cause of infant death. In a pilot study of 31 healthy pregnant women, we found that measurement of nine cell-free RNA (cfRNA) transcripts in maternal blood predicted gestational age with comparable accuracy to ultrasound but at substantially lower cost. In a related study of 38 women (23 full-term and 15 preterm deliveries), all at elevated risk of delivering preterm, we identified seven cfRNA transcripts that accurately classified women who delivered preterm up to 2 months in advance of labor. These tests hold promise for prenatal care in both the developed and developing worlds, although they require validation in larger, blinded clinical trials., (Copyright © 2018, American Association for the Advancement of Science.)
Published: 2018
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47. Genome-wide association study of Hirschsprung disease detects a novel low-frequency variant at the RET locus.

Author: Fadista J, Lund M, Skotte L, Geller F, Nandakumar P, Chatterjee S, Matsson H, Granström AL, Wester T, Salo P, Virtanen V, Carstensen L, Bybjerg-Grauholm J, Hougaard DM, Pakarinen M, Perola M, Nordenskjöld A, Chakravarti A, Melbye M, and Feenstra B
Subjects: Haplotypes, Humans, Hirschsprung Disease genetics, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-ret genetics
Abstract: Hirschsprung disease (HSCR) is a congenital disorder with a population incidence of ~1/5000 live births, defined by an absence of enteric ganglia along variable lengths of the colon. HSCR genome-wide association studies (GWAS) have found common associated variants at RET, SEMA3, and NRG1, but they still fail to explain all of its heritability. To enhance gene discovery, we performed a GWAS of 170 cases identified from the Danish nationwide pathology registry with 4717 controls, based on 6.2 million variants imputed from the haplotype reference consortium panel. We found a novel low-frequency variant (rs144432435), which, when conditioning on the lead RET single-nucleotide polymorphism (SNP), was of genome-wide significance in the discovery analysis. This conditional association signal was replicated in a Swedish HSCR cohort with discovery plus replication meta-analysis conditional odds ratio of 6.6 (P = 7.7 × 10 -10 ; 322 cases and 4893 controls). The conditional signal was, however, not replicated in two HSCR cohorts from USA and Finland, leading to the hypothesis that rs144432435 tags a rare haplotype present in Denmark and Sweden. Using the genome-wide complex trait analysis method, we estimated the SNP heritability of HSCR to be 88%, close to estimates based on classical family studies. Moreover, by using Lasso (least absolute shrinkage and selection operator) regression we were able to construct a genetic HSCR predictor with a area under the receiver operator characteristics curve of 76% in an independent validation set. In conclusion, we combined the largest collection of sporadic Hirschsprung cases to date (586 cases) to further elucidate HSCR's genetic architecture.
Published: 2018
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48. Maternal and fetal genetic contribution to gestational weight gain.

Author: Warrington NM, Richmond R, Fenstra B, Myhre R, Gaillard R, Paternoster L, Wang CA, Beaumont RN, Das S, Murcia M, Barton SJ, Espinosa A, Thiering E, Atalay M, Pitkänen N, Ntalla I, Jonsson AE, Freathy R, Karhunen V, Tiesler CMT, Allard C, Crawford A, Ring SM, Melbye M, Magnus P, Rivadeneira F, Skotte L, Hansen T, Marsh J, Guxens M, Holloway JW, Grallert H, Jaddoe VWV, Lowe WL Jr, Roumeliotaki T, Hattersley AT, Lindi V, Pahkala K, Panoutsopoulou K, Standl M, Flexeder C, Bouchard L, Aagaard Nohr E, Marina LS, Kogevinas M, Niinikoski H, Dedoussis G, Heinrich J, Reynolds RM, Lakka T, Zeggini E, Raitakari OT, Chatzi L, Inskip HM, Bustamante M, Hivert MF, Jarvelin MR, Sørensen TIA, Pennell C, Felix JF, Jacobsson B, Geller F, Evans DM, and Lawlor DA
Subjects: Female, Genome-Wide Association Study, Gestational Weight Gain physiology, Humans, Pregnancy physiology, Pregnancy statistics & numerical data, Fetus physiology, Gestational Weight Gain genetics, Pregnancy genetics
Abstract: Background: Clinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG., Participants and Methods: A genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10 543 mothers and 16 317 offspring of European origin, with replication in 10 660 mothers and 7561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (for example, maternal body mass index (BMI) and glucose, birth weight)., Results: Approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and the fetal genome made a surprisingly minor contribution to explain variation in GWG. Variants near the pregnancy-specific beta-1 glycoprotein 5 (PSG5) gene reached genome-wide significance (P=1.71 × 10 -8 ) for total GWG in the offspring genome, but did not replicate. Some established variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birth weight variants were largely unrelated to GWG., Conclusions: We found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outcomes may be due to the relationship of maternal BMI and diabetes with GWG.
Published: 2018
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49. Strabismus Incidence in a Danish Population-Based Cohort of Children.

Author: Torp-Pedersen T, Boyd HA, Skotte L, Haargaard B, Wohlfahrt J, Holmes JM, and Melbye M
Subjects: Age Distribution, Child, Child, Preschool, Cohort Studies, Denmark epidemiology, Ethnicity, Female, Humans, Incidence, Infant, Infant, Newborn, Male, Registries, Sex Distribution, Strabismus diagnosis, White People, Strabismus epidemiology
Abstract: Importance: To our knowledge, there have been few population-based studies of strabismus incidence conducted. Our population-based study provides valuable data for health services planning and identifying research needs., Objective: To determine the incidence and age distribution of strabismus, overall and by subtype, among children 7 years or younger., Design, Setting, and Participants: This population-based cohort study was conducted with data from 96 842 children enrolled in the Danish National Birth Cohort., Main Outcomes and Measures: Age-specific incidence and cumulative incidence and median age at the detection of strabismus, overall and by subtype., Results: The study cohort included 96 842 children born between 1996 and 2008 who are predominantly Caucasian and is composed of approximately 30% of births in Denmark, with a boy-girl ratio of 51:49. Overall, 1309 cases of strabismus were identified in the cohort. We found an overall cumulative strabismus incidence of 2.56% (95% CI, 2.42-2.69) at 7 years. The overall incidence was similar among boys and girls. Two hundred sixteen participants (16.5%) (95% CI, 14.5-18.6) had congenital esotropia, 177 (13.5%) (95% CI, 11.7-15.5) had fully accommodative esotropia, 252 (19.3%) (95% CI, 17.1-21.5) had partially accommodative esotropia, and 181 (13.8%) (95% CI, 12.0-15.8) had exotropia. The esotropia:exotropia ratio was 5.4:1 (95% CI, 3.4:1 to 7.5:1). Age-specific incidence curves for congenital esotropia, fully accommodative esotropia, partially accommodative esotropia, and all exotropia revealed interactions between strabismus subtype and age, suggesting that the different subtypes had different age-specific patterns of incidence (P < .001 for all comparisons between pairs of curves). The median age at detection for the 4 subtypes was 0, 32.0, 26.1, and 16.6 months, respectively., Conclusions and Relevance: In a national, population-based cohort study, we found a cumulative incidence of strabismus consistent with those reported in smaller European and American cohorts, but a somewhat higher esotropia:exotropia ratio than those that, to our knowledge, are typically reported by English and American studies. Patterns of incidence by age differed for different strabismus subtypes, indicating differences in age at onset and thereby implying differences in the underlying etiology.
Published: 2017
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50. CPT1A Missense Mutation Associated With Fatty Acid Metabolism and Reduced Height in Greenlanders.

Author: Skotte L, Koch A, Yakimov V, Zhou S, Søborg B, Andersson M, Michelsen SW, Navne JE, Mistry JM, Dion PA, Pedersen ML, Børresen ML, Rouleau GA, Geller F, Melbye M, and Feenstra B
Subjects: Alleles, Female, Gene Frequency, Genome-Wide Association Study, Genotype, Greenland, Humans, Inuit genetics, Male, Phenotype, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Body Size genetics, Carnitine O-Palmitoyltransferase genetics, Fatty Acids, Omega-3 metabolism, Mutation, Missense
Abstract: Background: Inuit have lived for thousands of years in an extremely cold environment on a diet dominated by marine-derived fat. To investigate how this selective pressure has affected the genetic regulation of fatty acid metabolism, we assessed 233 serum metabolic phenotypes in a population-based sample of 1570 Greenlanders., Methods and Results: Using array-based and targeted genotyping, we found that rs80356779, a p.Pro479Leu variant in CPT1A , was strongly associated with markers of n -3 fatty acid metabolism, including degree of unsaturation ( P =1.16×10 - 34 ), levels of polyunsaturated fatty acids, n -3 fatty acids, and docosahexaoenic acid relative to total fatty acid levels ( P =2.35×10 - 15 , P =4.02×10 - 19 , and P =7.92×10 - 27 ). The derived allele (L479) occurred at a frequency of 76.2% in our sample while being absent in most other populations, and we found strong signatures of positive selection at the locus. Furthermore, we found that each copy of L479 reduced height by an average of 2.1 cm ( P =1.04×10 - 9 ). In exome sequencing data from a sister population, the Nunavik Inuit, we found no other likely causal candidate variant than rs80356779., Conclusion: Our study shows that a common CPT1A missense mutation is strongly associated with a range of metabolic phenotypes and reduced height in Greenlanders. These findings are important from a public health perspective and highlight the usefulness of complex trait genetic studies in isolated populations., (© 2017 American Heart Association, Inc.)
Published: 2017
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