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Your search keyword '"Esko, Toñu"' showing total 17 results
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17 results on '"Esko, Toñu"'

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

Author

Feitosa, Mary F., Kraja, Aldi T., Chasman, Daniel I., Sung, Yun J., Winkler, Thomas W., Ntalla, Ioanna, Guo, Xiuqing, Franceschini, Nora, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Marten, Jonathan, Musani, Solomon K., Li, Changwei, Bentley, Amy R., Brown, Michael R., Schwander, Karen, Richard, Melissa A., Noordam, Raymond, Aschard, Hugues, Bartz, Traci M., Bielak, Lawrence F., Dorajoo, Rajkumar, Fisher, Virginia, Hartwig, Fernando P., Horimoto, Andrea R. V. R., Lohman, Kurt K., Manning, Alisa K., Rankinen, Tuomo, Smith, Albert V., Tajuddin, Salman M., Wojczynski, Mary K., Alver, Maris, Boissel, Mathilde, Cai, Qiuyin, Campbell, Archie, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gao, Chuan, Goel, Anuj, Hagemeijer, Yanick, Harris, Sarah E., He, Meian, Hsu, Fang-Chi, Jackson, Anne U., Kähönen, Mika, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Laguzzi, Federica, Luan, Jian'an, Matoba, Nana, Nolte, Ilja M., Padmanabhan, Sandosh, Riaz, Muhammad, Rueedi, Rico, Robino, Antonietta, Said, M. Abdullah, Scott, Robert A., Sofer, Tamar, Stančáková, Alena, Takeuchi, Fumihiko, Tayo, Bamidele O., van der Most, Peter J., Varga, Tibor V., Vitart, Veronique, Wang, Yajuan, Ware, Erin B., Warren, Helen R., Weiss, Stefan, Wen, Wanqing, Yanek, Lisa R., Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Amin, Najaf, Amini, Marzyeh, Arking, Dan E., Aung, Tin, Boerwinkle, Eric, Borecki, Ingrid, Broeckel, Ulrich, Brown, Morris, Brumat, Marco, Burke, Gregory L., Canouil, Mickaël, Chakravarti, Aravinda, Charumathi, Sabanayagam, Ida Chen, Yii-Der, Connell, John M., Correa, Adolfo, de las Fuentes, Lisa, de Mutsert, Renée, de Silva, H. Janaka, Deng, Xuan, Ding, Jingzhong, Duan, Qing, Eaton, Charles B., Ehret, Georg, Eppinga, Ruben N., Evangelou, Evangelos, Faul, Jessica D., Felix, Stephan B., Forouhi, Nita G., Forrester, Terrence, Franco, Oscar H., Friedlander, Yechiel, Gandin, Ilaria, Gao, He, Ghanbari, Mohsen, Gigante, Bruna, Gu, C. Charles, Gu, Dongfeng, Hagenaars, Saskia P., Hallmans, Göran, Harris, Tamara B., He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hirata, Makoto, Howard, Barbara V., Ikram, M. Arfan, John, Ulrich, Katsuya, Tomohiro, Khor, Chiea Chuen, Kilpeläinen, Tuomas O., Koh, Woon-Puay, Krieger, José E., Kritchevsky, Stephen B., Kubo, Michiaki, Kuusisto, Johanna, Lakka, Timo A., Langefeld, Carl D., Langenberg, Claudia, Launer, Lenore J., Lehne, Benjamin, Lewis, Cora E., Li, Yize, Lin, Shiow, Liu, Jianjun, Liu, Jingmin, Loh, Marie, Louie, Tin, Mägi, Reedik, McKenzie, Colin A., Meitinger, Thomas, Metspalu, Andres, Milaneschi, Yuri, Milani, Lili, Mohlke, Karen L., Momozawa, Yukihide, Nalls, Mike A., Nelson, Christopher P., Sotoodehnia, Nona, Norris, Jill M., O'Connell, Jeff R., Palmer, Nicholette D., Perls, Thomas, Pedersen, Nancy L., Peters, Annette, Peyser, Patricia A., Poulter, Neil, Raffel, Leslie J., Raitakari, Olli T., Roll, Kathryn, Rose, Lynda M., Rosendaal, Frits R., Rotter, Jerome I., Schmidt, Carsten O., Schreiner, Pamela J., Schupf, Nicole, Scott, William R., Sever, Peter S., Shi, Yuan, Sidney, Stephen, Sims, Mario, Sitlani, Colleen M., Smith, Jennifer A., Snieder, Harold, Starr, John M., Strauch, Konstantin, Stringham, Heather M., Tan, Nicholas Y. Q., Tang, Hua, Taylor, Kent D., Teo, Yik Ying, Tham, Yih Chung, Turner, Stephen T., Uitterlinden, André G., Vollenweider, Peter, Waldenberger, Melanie, Wang, Lihua, Wang, Ya Xing, Wei, Wen Bin, Williams, Christine, Yao, Jie, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B., Becker, Diane M., Boehnke, Michael, Bowden, Donald W., Chambers, John C., Deary, Ian J., Esko, Tõnu, Farrall, Martin, Franks, Paul W., Freedman, Barry I., Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Jonas, Jost Bruno, Kamatani, Yoichiro, Kato, Norihiro, Kooner, Jaspal S., Kutalik, Zoltán, Laakso, Markku, Laurie, Cathy C., Leander, Karin, Lehtimäki, Terho, Study, Lifelines Cohort, Magnusson, Patrik K. E., Oldehinkel, Albertine J., Penninx, Brenda W. J. H., Polasek, Ozren, Porteous, David J., Rauramaa, Rainer, Samani, Nilesh J., Scott, James, Shu, Xiao-Ou, van der Harst, Pim, Wagenknecht, Lynne E., Wareham, Nicholas J., Watkins, Hugh, Weir, David R., Wickremasinghe, Ananda R., Wu, Tangchun, Zheng, Wei, Bouchard, Claude, Christensen, Kaare, Evans, Michele K., Gudnason, Vilmundur, Horta, Bernardo L., Kardia, Sharon L. R., Liu, Yongmei, Pereira, Alexandre C., Psaty, Bruce M., Ridker, Paul M., van Dam, Rob M., Gauderman, W. James, Zhu, Xiaofeng, Mook-Kanamori, Dennis O., Fornage, Myriam, Rotimi, Charles N., Cupples, L. Adrienne, Kelly, Tanika N., Fox, Ervin R., Hayward, Caroline, van Duijn, Cornelia M., Tai, E Shyong, Wong, Tien Yin, Kooperberg, Charles, Palmas, Walter, Rice, Kenneth, Morrison, Alanna C., Elliott, Paul, Caulfield, Mark J., Munroe, Patricia B., Rao, Dabeeru C., Province, Michael A., and Levy, Daniel

Subjects
Biology and Life Sciences, Nutrition, Diet, Alcohol Consumption, Medicine and Health Sciences, Mathematical and Statistical Techniques, Statistical Methods, Meta-Analysis, Physical Sciences, Mathematics, Statistics (Mathematics), Computational Biology, Genome Complexity, Introns, Genetics, Genomics, Vascular Medicine, Blood Pressure, Genetic Loci, Molecular Biology, Molecular Biology Techniques, Gene Mapping, Alleles, Psychology, Addiction, Alcoholism, Social Sciences, Mental Health and Psychiatry, Substance-Related Disorders, Public and Occupational Health
Abstract

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10−5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10−8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10−8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

Published
2018
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2. Genome-wide physical activity interactions in adiposity ― A meta-analysis of 200,452 adults

Author

Graff, Mariaelisa, Scott, Robert A., Justice, Anne E., Young, Kristin L., Feitosa, Mary F., Barata, Llilda, Winkler, Thomas W., Chu, Audrey Y., Mahajan, Anubha, Hadley, David, Xue, Luting, Workalemahu, Tsegaselassie, Heard-Costa, Nancy L., den Hoed, Marcel, Ahluwalia, Tarunveer S., Qi, Qibin, Ngwa, Julius S., Renström, Frida, Quaye, Lydia, Eicher, John D., Hayes, James E., Cornelis, Marilyn, Kutalik, Zoltan, Lim, Elise, Luan, Jian’an, Huffman, Jennifer E., Zhang, Weihua, Zhao, Wei, Griffin, Paula J., Haller, Toomas, Ahmad, Shafqat, Marques-Vidal, Pedro M., Bien, Stephanie, Yengo, Loic, Teumer, Alexander, Smith, Albert Vernon, Kumari, Meena, Harder, Marie Neergaard, Justesen, Johanne Marie, Kleber, Marcus E., Hollensted, Mette, Lohman, Kurt, Rivera, Natalia V., Whitfield, John B., Zhao, Jing Hua, Stringham, Heather M., Lyytikäinen, Leo-Pekka, Huppertz, Charlotte, Willemsen, Gonneke, Peyrot, Wouter J., Wu, Ying, Kristiansson, Kati, Demirkan, Ayse, Fornage, Myriam, Hassinen, Maija, Bielak, Lawrence F., Cadby, Gemma, Tanaka, Toshiko, Mägi, Reedik, van der Most, Peter J., Jackson, Anne U., Bragg-Gresham, Jennifer L., Vitart, Veronique, Marten, Jonathan, Navarro, Pau, Bellis, Claire, Pasko, Dorota, Johansson, Åsa, Snitker, Søren, Cheng, Yu-Ching, Eriksson, Joel, Lim, Unhee, Aadahl, Mette, Adair, Linda S., Amin, Najaf, Balkau, Beverley, Auvinen, Juha, Beilby, John, Bergman, Richard N., Bergmann, Sven, Bertoni, Alain G., Blangero, John, Bonnefond, Amélie, Bonnycastle, Lori L., Borja, Judith B., Brage, Søren, Busonero, Fabio, Buyske, Steve, Campbell, Harry, Chines, Peter S., Collins, Francis S., Corre, Tanguy, Smith, George Davey, Delgado, Graciela E., Dueker, Nicole, Dörr, Marcus, Ebeling, Tapani, Eiriksdottir, Gudny, Esko, Tõnu, Faul, Jessica D., Fu, Mao, Færch, Kristine, Gieger, Christian, Gläser, Sven, Gong, Jian, Gordon-Larsen, Penny, Grallert, Harald, Grammer, Tanja B., Grarup, Niels, van Grootheest, Gerard, Harald, Kennet, Hastie, Nicholas D., Havulinna, Aki S., Hernandez, Dena, Hindorff, Lucia, Hocking, Lynne J., Holmens, Oddgeir L., Holzapfel, Christina, Hottenga, Jouke Jan, Huang, Jie, Huang, Tao, Hui, Jennie, Huth, Cornelia, Hutri-Kähönen, Nina, James, Alan L., Jansson, John-Olov, Jhun, Min A., Juonala, Markus, Kinnunen, Leena, Koistinen, Heikki A., Kolcic, Ivana, Komulainen, Pirjo, Kuusisto, Johanna, Kvaløy, Kirsti, Kähönen, Mika, Lakka, Timo A., Launer, Lenore J., Lehne, Benjamin, Lindgren, Cecilia M., Lorentzon, Mattias, Luben, Robert, Marre, Michel, Milaneschi, Yuri, Monda, Keri L., Montgomery, Grant W., De Moor, Marleen H. M., Mulas, Antonella, Müller-Nurasyid, Martina, Musk, A. W., Männikkö, Reija, Männistö, Satu, Narisu, Narisu, Nauck, Matthias, Nettleton, Jennifer A., Nolte, Ilja M., Oldehinkel, Albertine J., Olden, Matthias, Ong, Ken K., Padmanabhan, Sandosh, Paternoster, Lavinia, Perez, Jeremiah, Perola, Markus, Peters, Annette, Peters, Ulrike, Peyser, Patricia A., Prokopenko, Inga, Puolijoki, Hannu, Raitakari, Olli T., Rankinen, Tuomo, Rasmussen-Torvik, Laura J., Rawal, Rajesh, Ridker, Paul M., Rose, Lynda M., Rudan, Igor, Sarti, Cinzia, Sarzynski, Mark A., Savonen, Kai, Scott, William R., Sanna, Serena, Shuldiner, Alan R., Sidney, Steve, Silbernagel, Günther, Smith, Blair H., Smith, Jennifer A., Snieder, Harold, Stančáková, Alena, Sternfeld, Barbara, Swift, Amy J., Tammelin, Tuija, Tan, Sian-Tsung, Thorand, Barbara, Thuillier, Dorothée, Vandenput, Liesbeth, Vestergaard, Henrik, van Vliet-Ostaptchouk, Jana V., Vohl, Marie-Claude, Völker, Uwe, Waeber, Gérard, Walker, Mark, Wild, Sarah, Wong, Andrew, Wright, Alan F., Zillikens, M. Carola, Zubair, Niha, Haiman, Christopher A., Lemarchand, Loic, Gyllensten, Ulf, Ohlsson, Claes, Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, André G., Pérusse, Louis, Wilson, James F., Hayward, Caroline, Polasek, Ozren, Cucca, Francesco, Hveem, Kristian, Hartman, Catharina A., Tönjes, Anke, Bandinelli, Stefania, Palmer, Lyle J., Kardia, Sharon L. R., Rauramaa, Rainer, Sørensen, Thorkild I. A., Tuomilehto, Jaakko, Salomaa, Veikko, Penninx, Brenda W. J. H., de Geus, Eco J. C., Boomsma, Dorret I., Lehtimäki, Terho, Mangino, Massimo, Laakso, Markku, Bouchard, Claude, Martin, Nicholas G., Kuh, Diana, Liu, Yongmei, Linneberg, Allan, März, Winfried, Strauch, Konstantin, Kivimäki, Mika, Harris, Tamara B., Gudnason, Vilmundur, Völzke, Henry, Qi, Lu, Järvelin, Marjo-Riitta, Chambers, John C., Kooner, Jaspal S., Froguel, Philippe, Kooperberg, Charles, Vollenweider, Peter, Hallmans, Göran, Hansen, Torben, Pedersen, Oluf, Metspalu, Andres, Wareham, Nicholas J., Langenberg, Claudia, Weir, David R., Porteous, David J., Boerwinkle, Eric, Chasman, Daniel I., Abecasis, Gonçalo R., Barroso, Inês, McCarthy, Mark I., Frayling, Timothy M., O’Connell, Jeffrey R., van Duijn, Cornelia M., Boehnke, Michael, Heid, Iris M., Mohlke, Karen L., Strachan, David P., Fox, Caroline S., Liu, Ching-Ti, Hirschhorn, Joel N., Klein, Robert J., Johnson, Andrew D., Borecki, Ingrid B., Franks, Paul W., North, Kari E., Cupples, L. Adrienne, Loos, Ruth J. F., and Kilpeläinen, Tuomas O.

Subjects
Mathematical and Statistical Techniques, Statistical Methods, Meta-Analysis, Physical Sciences, Mathematics, Statistics (Mathematics), Medicine and Health Sciences, Public and Occupational Health, Physical Activity, Biology and Life Sciences, Genetics, Genetic Loci, Computational Biology, Genome Analysis, Genome-Wide Association Studies, Genomics, Human Genetics, Physiology, Physiological Parameters, Body Weight, Obesity, Functional Genomics, Epigenomics, Cell Biology, Signal Transduction, Cell Signaling, Genomic Signal Processing
Abstract

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

Published
2017
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3. Pathogenic implications for autoimmune mechanisms derived by comparative eQTL analysis of CD4+ versus CD8+ T cells

Author

Kasela, Silva, Kisand, Kai, Tserel, Liina, Kaleviste, Epp, Remm, Anu, Fischer, Krista, Esko, Tõnu, Westra, Harm-Jan, Fairfax, Benjamin P., Makino, Seiko, Knight, Julian C., Franke, Lude, Metspalu, Andres, Peterson, Pärt, and Milani, Lili

Subjects
Biology and Life Sciences, Cell Biology, Cellular Types, Animal Cells, Blood Cells, White Blood Cells, T Cells, Immune Cells, Immunology, Medicine and Health Sciences, Biology and life sciences, Cell biology, Cellular types, Animal cells, Blood cells, White blood cells, T cells, Cytotoxic T cells, Immune cells, Medicine and health sciences, Genetics, Gene Expression, Chromosome biology, Chromatin, Chromatin modification, DNA methylation, Epigenetics, Gene expression, DNA, DNA modification, Biochemistry, Nucleic acids, Gene Regulation, Computational Biology, Genome Analysis, Genome-Wide Association Studies, Genomics, Human Genetics, Genetic Loci, Molecular Biology, Molecular Biology Techniques, Gene Mapping
Abstract

Inappropriate activation or inadequate regulation of CD4+ and CD8+ T cells may contribute to the initiation and progression of multiple autoimmune and inflammatory diseases. Studies on disease-associated genetic polymorphisms have highlighted the importance of biological context for many regulatory variants, which is particularly relevant in understanding the genetic regulation of the immune system and its cellular phenotypes. Here we show cell type-specific regulation of transcript levels of genes associated with several autoimmune diseases in CD4+ and CD8+ T cells including a trans-acting regulatory locus at chr12q13.2 containing the rs1131017 SNP in the RPS26 gene. Most remarkably, we identify a common missense variant in IL27, associated with type 1 diabetes that results in decreased functional activity of the protein and reduced expression levels of downstream IRF1 and STAT1 in CD4+ T cells only. Altogether, our results indicate that eQTL mapping in purified T cells provides novel functional insights into polymorphisms and pathways associated with autoimmune diseases.

Published
2017
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4. Ancient Haplotypes at the 15q24.2 Microdeletion Region Are Linked to Brain Expression of MAN2C1 and Children's Intelligence

Author

Cáceres, Alejandro, Esko, Tõnu, Pappa, Irene, Gutiérrez, Armand, Lopez-Espinosa, Maria-Jose, Llop, Sabrina, Bustamante, Mariona, Tiemeier, Henning, Metspalu, Andres, Joshi, Peter K., Wilsonx, James F., Reina-Castillón, Judith, Shin, Jean, Pausova, Zdenka, Paus, Tomáš, Sunyer, Jordi, Pérez-Jurado, Luis A., and González, Juan R.

Subjects
Biology and Life Sciences, Evolutionary Biology, Population Genetics, Haplotypes, Genetics, Population Biology, Gene Expression, Psychology, Developmental Psychology, Autism Spectrum Disorder, Autism, Social Sciences, Neuroscience, Developmental Neuroscience, Neurodevelopmental Disorders, Medicine and Health Sciences, Neurology, People and Places, Population Groupings, Age Groups, Children, Families, Cognitive Science, Cognitive Neuroscience, Cognitive Neurology, Cognitive Impairment, Computational Biology, Genome Analysis, Genomic Libraries, Genomics, Heredity, Homozygosity, Geographical Locations, Africa, Ethiopia
Abstract

The chromosome bands 15q24.1-15q24.3 contain a complex region with numerous segmental duplications that predispose to regional microduplications and microdeletions, both of which have been linked to intellectual disability, speech delay and autistic features. The region may also harbour common inversion polymorphisms whose functional and phenotypic manifestations are unknown. Using single nucleotide polymorphism (SNP) data, we detected four large contiguous haplotype-genotypes at 15q24 with Mendelian inheritance in 2,562 trios, African origin, high population stratification and reduced recombination rates. Although the haplotype-genotypes have been most likely generated by decreased or absent recombination among them, we could not confirm that they were the product of inversion polymorphisms in the region. One of the blocks was composed of three haplotype-genotypes (N1a, N1b and N2), which significantly correlated with intelligence quotient (IQ) in 2,735 children of European ancestry from three independent population cohorts. Homozygosity for N2 was associated with lower verbal IQ (2.4-point loss, p-value = 0.01), while homozygosity for N1b was associated with 3.2-point loss in non-verbal IQ (p-value = 0.0006). The three alleles strongly correlated with expression levels of MAN2C1 and SNUPN in blood and brain. Homozygosity for N2 correlated with over-expression of MAN2C1 over many brain areas but the occipital cortex where N1b homozygous highly under-expressed. Our population-based analyses suggest that MAN2C1 may contribute to the verbal difficulties observed in microduplications and to the intellectual disability of microdeletion syndromes, whose characteristic dosage increment and removal may affect different brain areas.

Published
2016
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5. Altered Gene Expression Associated with microRNA Binding Site Polymorphisms

Author

Võsa, Urmo, Esko, Tõnu, Kasela, Silva, and Annilo, Tarmo

Abstract

Allele-specific gene expression associated with genetic variation in regulatory regions can play an important role in the development of complex traits. We hypothesized that polymorphisms in microRNA (miRNA) response elements (MRE-SNPs) that either disrupt a miRNA binding site or create a new miRNA binding site can affect the allele-specific expression of target genes. By integrating public expression quantitative trait locus (eQTL) data, miRNA binding site predictions, small RNA sequencing, and Argonaute crosslinking immunoprecipitation (AGO-CLIP) datasets, we identified genetic variants that can affect gene expression by modulating miRNA binding efficiency. We also identified MRE-SNPs located in regions associated with complex traits, indicating possible causative mechanisms associated with these loci. The results of this study expand the current understanding of gene expression regulation and help to interpret the mechanisms underlying eQTL effects.

Published
2015
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6. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Author

Winkler, Thomas W., Justice, Anne E., Graff, Mariaelisa, Barata, Llilda, Feitosa, Mary F., Chu, Su, Czajkowski, Jacek, Esko, Tõnu, Fall, Tove, Kilpeläinen, Tuomas O., Lu, Yingchang, Mägi, Reedik, Mihailov, Evelin, Pers, Tune H., Rüeger, Sina, Teumer, Alexander, Ehret, Georg B., Ferreira, Teresa, Heard-Costa, Nancy L., Karjalainen, Juha, Lagou, Vasiliki, Mahajan, Anubha, Neinast, Michael D., Prokopenko, Inga, Simino, Jeannette, Teslovich, Tanya M., Jansen, Rick, Westra, Harm-Jan, White, Charles C., Absher, Devin, Ahluwalia, Tarunveer S., Ahmad, Shafqat, Albrecht, Eva, Alves, Alexessander Couto, Bragg-Gresham, Jennifer L., de Craen, Anton J. M., Bis, Joshua C., Bonnefond, Amélie, Boucher, Gabrielle, Cadby, Gemma, Cheng, Yu-Ching, Chiang, Charleston W. K., Delgado, Graciela, Demirkan, Ayse, Dueker, Nicole, Eklund, Niina, Eiriksdottir, Gudny, Eriksson, Joel, Feenstra, Bjarke, Fischer, Krista, Frau, Francesca, Galesloot, Tessel E., Geller, Frank, Goel, Anuj, Gorski, Mathias, Grammer, Tanja B., Gustafsson, Stefan, Haitjema, Saskia, Hottenga, Jouke-Jan, Huffman, Jennifer E., Jackson, Anne U., Jacobs, Kevin B., Johansson, Åsa, Kaakinen, Marika, Kleber, Marcus E., Lahti, Jari, Leach, Irene Mateo, Lehne, Benjamin, Liu, Youfang, Lo, Ken Sin, Lorentzon, Mattias, Luan, Jian'an, Madden, Pamela A. F., Mangino, Massimo, McKnight, Barbara, Medina-Gomez, Carolina, Monda, Keri L., Montasser, May E., Müller, Gabriele, Müller-Nurasyid, Martina, Nolte, Ilja M., Panoutsopoulou, Kalliope, Pascoe, Laura, Paternoster, Lavinia, Rayner, Nigel W., Renström, Frida, Rizzi, Federica, Rose, Lynda M., Ryan, Kathy A., Salo, Perttu, Sanna, Serena, Scharnagl, Hubert, Shi, Jianxin, Smith, Albert Vernon, Southam, Lorraine, Stančáková, Alena, Steinthorsdottir, Valgerdur, Strawbridge, Rona J., Sung, Yun Ju, Tachmazidou, Ioanna, Tanaka, Toshiko, Thorleifsson, Gudmar, Trompet, Stella, Pervjakova, Natalia, Tyrer, Jonathan P., Vandenput, Liesbeth, van der Laan, Sander W, van der Velde, Nathalie, van Setten, Jessica, van Vliet-Ostaptchouk, Jana V., Verweij, Niek, Vlachopoulou, Efthymia, Waite, Lindsay L., Wang, Sophie R., Wang, Zhaoming, Wild, Sarah H., Willenborg, Christina, Wilson, James F., Wong, Andrew, Yang, Jian, Yengo, Loïc, Yerges-Armstrong, Laura M., Yu, Lei, Zhang, Weihua, Zhao, Jing Hua, Andersson, Ehm A., Bakker, Stephan J. L., Baldassarre, Damiano, Banasik, Karina, Barcella, Matteo, Barlassina, Cristina, Bellis, Claire, Benaglio, Paola, Blangero, John, Blüher, Matthias, Bonnet, Fabrice, Bonnycastle, Lori L., Boyd, Heather A., Bruinenberg, Marcel, Buchman, Aron S, Campbell, Harry, Chen, Yii-Der Ida, Chines, Peter S., Claudi-Boehm, Simone, Cole, John, Collins, Francis S., de Geus, Eco J. C., de Groot, Lisette C. P. G. M., Dimitriou, Maria, Duan, Jubao, Enroth, Stefan, Eury, Elodie, Farmaki, Aliki-Eleni, Forouhi, Nita G., Friedrich, Nele, Gejman, Pablo V., Gigante, Bruna, Glorioso, Nicola, Go, Alan S., Gottesman, Omri, Gräßler, Jürgen, Grallert, Harald, Grarup, Niels, Gu, Yu-Mei, Broer, Linda, Ham, Annelies C., Hansen, Torben, Harris, Tamara B., Hartman, Catharina A., Hassinen, Maija, Hastie, Nicholas, Hattersley, Andrew T., Heath, Andrew C., Henders, Anjali K., Hernandez, Dena, Hillege, Hans, Holmen, Oddgeir, Hovingh, Kees G, Hui, Jennie, Husemoen, Lise L., Hutri-Kähönen, Nina, Hysi, Pirro G., Illig, Thomas, De Jager, Philip L., Jalilzadeh, Shapour, Jørgensen, Torben, Jukema, J. Wouter, Juonala, Markus, Kanoni, Stavroula, Karaleftheri, Maria, Khaw, Kay Tee, Kinnunen, Leena, Kittner, Steven J., Koenig, Wolfgang, Kolcic, Ivana, Kovacs, Peter, Krarup, Nikolaj T., Kratzer, Wolfgang, Krüger, Janine, Kuh, Diana, Kumari, Meena, Kyriakou, Theodosios, Langenberg, Claudia, Lannfelt, Lars, Lanzani, Chiara, Lotay, Vaneet, Launer, Lenore J., Leander, Karin, Lindström, Jaana, Linneberg, Allan, Liu, Yan-Ping, Lobbens, Stéphane, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Magnusson, Patrik K., McArdle, Wendy L., Menni, Cristina, Merger, Sigrun, Milani, Lili, Montgomery, Grant W., Morris, Andrew P., Narisu, Narisu, Nelis, Mari, Ong, Ken K., Palotie, Aarno, Pérusse, Louis, Pichler, Irene, Pilia, Maria G., Pouta, Anneli, Rheinberger, Myriam, Ribel-Madsen, Rasmus, Richards, Marcus, Rice, Kenneth M., Rice, Treva K., Rivolta, Carlo, Salomaa, Veikko, Sanders, Alan R., Sarzynski, Mark A., Scholtens, Salome, Scott, Robert A., Scott, William R., Sebert, Sylvain, Sengupta, Sebanti, Sennblad, Bengt, Seufferlein, Thomas, Silveira, Angela, Slagboom, P. Eline, Smit, Jan H., Sparsø, Thomas H., Stirrups, Kathleen, Stolk, Ronald P., Stringham, Heather M., Swertz, Morris A, Swift, Amy J., Syvänen, Ann-Christine, Tan, Sian-Tsung, Thorand, Barbara, Tönjes, Anke, Tremblay, Angelo, Tsafantakis, Emmanouil, van der Most, Peter J., Völker, Uwe, Vohl, Marie-Claude, Vonk, Judith M., Waldenberger, Melanie, Walker, Ryan W., Wennauer, Roman, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Wright, Alan F., Zillikens, M. Carola, van Dijk, Suzanne C., van Schoor, Natasja M., Asselbergs, Folkert W., de Bakker, Paul I. W., Beckmann, Jacques S., Beilby, John, Bennett, David A., Bergman, Richard N., Bergmann, Sven, Böger, Carsten A., Boehm, Bernhard O., Boerwinkle, Eric, Boomsma, Dorret I., Bornstein, Stefan R., Bottinger, Erwin P., Bouchard, Claude, Chambers, John C., Chanock, Stephen J., Chasman, Daniel I., Cucca, Francesco, Cusi, Daniele, Dedoussis, George, Erdmann, Jeanette, Eriksson, Johan G., Evans, Denis A., de Faire, Ulf, Farrall, Martin, Ferrucci, Luigi, Ford, Ian, Franke, Lude, Franks, Paul W., Froguel, Philippe, Gansevoort, Ron T., Gieger, Christian, Grönberg, Henrik, Gudnason, Vilmundur, Gyllensten, Ulf, Hall, Per, Hamsten, Anders, van der Harst, Pim, Hayward, Caroline, Heliövaara, Markku, Hengstenberg, Christian, Hicks, Andrew A, Hingorani, Aroon, Hofman, Albert, Hu, Frank, Huikuri, Heikki V., Hveem, Kristian, James, Alan L., Jordan, Joanne M., Jula, Antti, Kähönen, Mika, Kajantie, Eero, Kathiresan, Sekar, Kiemeney, Lambertus A. L. M., Kivimaki, Mika, Knekt, Paul B., Koistinen, Heikki A., Kooner, Jaspal S., Koskinen, Seppo, Kuusisto, Johanna, Maerz, Winfried, Martin, Nicholas G, Laakso, Markku, Lakka, Timo A., Lehtimäki, Terho, Lettre, Guillaume, Levinson, Douglas F., Lind, Lars, Lokki, Marja-Liisa, Mäntyselkä, Pekka, Melbye, Mads, Metspalu, Andres, Mitchell, Braxton D., Moll, Frans L., Murray, Jeffrey C., Musk, Arthur W., Nieminen, Markku S., Njølstad, Inger, Ohlsson, Claes, Oldehinkel, Albertine J., Oostra, Ben A., Palmer, Lyle J, Pankow, James S., Pasterkamp, Gerard, Pedersen, Nancy L., Pedersen, Oluf, Penninx, Brenda W., Perola, Markus, Peters, Annette, Polašek, Ozren, Pramstaller, Peter P., Psaty, Bruce M., Qi, Lu, Quertermous, Thomas, Raitakari, Olli T., Rankinen, Tuomo, Rauramaa, Rainer, Ridker, Paul M., Rioux, John D., Rivadeneira, Fernando, Rotter, Jerome I., Rudan, Igor, den Ruijter, Hester M., Saltevo, Juha, Sattar, Naveed, Schunkert, Heribert, Schwarz, Peter E. H., Shuldiner, Alan R., Sinisalo, Juha, Snieder, Harold, Sørensen, Thorkild I. A., Spector, Tim D., Staessen, Jan A., Stefania, Bandinelli, Thorsteinsdottir, Unnur, Stumvoll, Michael, Tardif, Jean-Claude, Tremoli, Elena, Tuomilehto, Jaakko, Uitterlinden, André G., Uusitupa, Matti, Verbeek, André L. M., Vermeulen, Sita H., Viikari, Jorma S., Vitart, Veronique, Völzke, Henry, Vollenweider, Peter, Waeber, Gérard, Walker, Mark, Wallaschofski, Henri, Wareham, Nicholas J., Watkins, Hugh, Zeggini, Eleftheria, Chakravarti, Aravinda, Clegg, Deborah J., Cupples, L. Adrienne, Gordon-Larsen, Penny, Jaquish, Cashell E., Rao, D. C., Abecasis, Goncalo R., Assimes, Themistocles L., Barroso, Inês, Berndt, Sonja I., Boehnke, Michael, Deloukas, Panos, Fox, Caroline S., Groop, Leif C., Hunter, David J., Ingelsson, Erik, Kaplan, Robert C., McCarthy, Mark I., Mohlke, Karen L., O'Connell, Jeffrey R., Schlessinger, David, Strachan, David P., Stefansson, Kari, van Duijn, Cornelia M., Hirschhorn, Joel N., Lindgren, Cecilia M., Heid, Iris M., North, Kari E., Borecki, Ingrid B., Kutalik, Zoltán, and Loos, Ruth J. F.

Abstract

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

Published
2015
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7. Functional Impact and Evolution of a Novel Human Polymorphic Inversion That Disrupts a Gene and Creates a Fusion Transcript

Author

Puig, Marta, Castellano, David, Pantano, Lorena, Giner-Delgado, Carla, Izquierdo, David, Gayà-Vidal, Magdalena, Lucas-Lledó, José Ignacio, Esko, Tõnu, Terao, Chikashi, Matsuda, Fumihiko, and Cáceres, Mario

Abstract

Despite many years of study into inversions, very little is known about their functional consequences, especially in humans. A common hypothesis is that the selective value of inversions stems in part from their effects on nearby genes, although evidence of this in natural populations is almost nonexistent. Here we present a global analysis of a new 415-kb polymorphic inversion that is among the longest ones found in humans and is the first with clear position effects. This inversion is located in chromosome 19 and has been generated by non-homologous end joining between blocks of transposable elements with low identity. PCR genotyping in 541 individuals from eight different human populations allowed the detection of tag SNPs and inversion genotyping in multiple populations worldwide, showing that the inverted allele is mainly found in East Asia with an average frequency of 4.7%. Interestingly, one of the breakpoints disrupts the transcription factor gene ZNF257, causing a significant reduction in the total expression level of this gene in lymphoblastoid cell lines. RNA-Seq analysis of the effects of this expression change in standard homozygotes and inversion heterozygotes revealed distinct expression patterns that were validated by quantitative RT-PCR. Moreover, we have found a new fusion transcript that is generated exclusively from inverted chromosomes around one of the breakpoints. Finally, by the analysis of the associated nucleotide variation, we have estimated that the inversion was generated ~40,000–50,000 years ago and, while a neutral evolution cannot be ruled out, its current frequencies are more consistent with those expected for a deleterious variant, although no significant association with phenotypic traits has been found so far.

Published
2015
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8. A Meta-analysis of Gene Expression Signatures of Blood Pressure and Hypertension

Author

Huan, Tianxiao, Esko, Tõnu, Peters, Marjolein J., Pilling, Luke C., Schramm, Katharina, Schurmann, Claudia, Chen, Brian H., Liu, Chunyu, Joehanes, Roby, Johnson, Andrew D., Yao, Chen, Ying, Sai-xia, Courchesne, Paul, Milani, Lili, Raghavachari, Nalini, Wang, Richard, Liu, Poching, Reinmaa, Eva, Dehghan, Abbas, Hofman, Albert, Uitterlinden, André G., Hernandez, Dena G., Bandinelli, Stefania, Singleton, Andrew, Melzer, David, Metspalu, Andres, Carstensen, Maren, Grallert, Harald, Herder, Christian, Meitinger, Thomas, Peters, Annette, Roden, Michael, Waldenberger, Melanie, Dörr, Marcus, Felix, Stephan B., Zeller, Tanja, Vasan, Ramachandran, O'Donnell, Christopher J., Munson, Peter J., Yang, Xia, Prokisch, Holger, Völker, Uwe, van Meurs, Joyce B. J., Ferrucci, Luigi, and Levy, Daniel

Abstract

Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p<0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%–9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension.

Published
2015
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9. Within-Trait Heterogeneity in Age Group Differences in Personality Domains and Facets: Implications for the Development and Coherence of Personality Traits

Author

Mõttus, René, Realo, Anu, Allik, Jüri, Esko, Tõnu, Metspalu, Andres, and Johnson, Wendy

Abstract

The study investigated differences in the Five-Factor Model (FFM) domains and facets across adulthood. The main questions were whether personality scales reflected coherent units of trait development and thereby coherent personality traits more generally. These questions were addressed by testing if the components of the trait scales (items for facet scales and facets for domain scales) showed consistent age group differences. For this, measurement invariance (MI) framework was used. In a sample of 2,711 Estonians who had completed the NEO Personality Inventory 3 (NEO PI-3), more than half of the facet scales and one domain scale did not meet the criterion for weak MI (factor loading equality) across 12 age groups spanning ages from 18 to 91 years. Furthermore, none of the facet and domain scales met the criterion for strong MI (intercept equality), suggesting that items of the same facets and facets of the same domains varied in age group differences. When items were residualized for their respective facets, 46% of them had significant (p < 0.0002) residual age-correlations. When facets were residualized for their domain scores, a majority had significant (p < 0.002) residual age-correlations. For each domain, a series of latent factors were specified using random quarters of their items: scores of such latent factors varied notably (within domains) in correlations with age. We argue that manifestations of aetiologically coherent traits should show similar age group differences. Given this, the FFM domains and facets as embodied in the NEO PI-3 do not reflect aetiologically coherent traits.

Published
2015
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10. Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation

Author

Horikoshi, Momoko, Mӓgi, Reedik, van de Bunt, Martijn, Surakka, Ida, Sarin, Antti-Pekka, Mahajan, Anubha, Marullo, Letizia, Thorleifsson, Gudmar, Hӓgg, Sara, Hottenga, Jouke-Jan, Ladenvall, Claes, Ried, Janina S., Winkler, Thomas W., Willems, Sara M., Pervjakova, Natalia, Esko, Tõnu, Beekman, Marian, Nelson, Christopher P., Willenborg, Christina, Wiltshire, Steven, Ferreira, Teresa, Fernandez, Juan, Gaulton, Kyle J., Steinthorsdottir, Valgerdur, Hamsten, Anders, Magnusson, Patrik K. E., Willemsen, Gonneke, Milaneschi, Yuri, Robertson, Neil R., Groves, Christopher J., Bennett, Amanda J., Lehtimӓki, Terho, Viikari, Jorma S., Rung, Johan, Lyssenko, Valeriya, Perola, Markus, Heid, Iris M., Herder, Christian, Grallert, Harald, Müller-Nurasyid, Martina, Roden, Michael, Hypponen, Elina, Isaacs, Aaron, van Leeuwen, Elisabeth M., Karssen, Lennart C., Mihailov, Evelin, Houwing-Duistermaat, Jeanine J., de Craen, Anton J. M., Deelen, Joris, Havulinna, Aki S., Blades, Matthew, Hengstenberg, Christian, Erdmann, Jeanette, Schunkert, Heribert, Kaprio, Jaakko, Tobin, Martin D., Samani, Nilesh J., Lind, Lars, Salomaa, Veikko, Lindgren, Cecilia M., Slagboom, P. Eline, Metspalu, Andres, van Duijn, Cornelia M., Eriksson, Johan G., Peters, Annette, Gieger, Christian, Jula, Antti, Groop, Leif, Raitakari, Olli T., Power, Chris, Penninx, Brenda W. J. H., de Geus, Eco, Smit, Johannes H., Boomsma, Dorret I., Pedersen, Nancy L., Ingelsson, Erik, Thorsteinsdottir, Unnur, Stefansson, Kari, Ripatti, Samuli, Prokopenko, Inga, McCarthy, Mark I., and Morris, Andrew P.

Abstract

Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.

Published
2015
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11. Cell Specific eQTL Analysis without Sorting Cells

Author

Westra, Harm-Jan, Arends, Danny, Esko, Tõnu, Peters, Marjolein J., Schurmann, Claudia, Schramm, Katharina, Kettunen, Johannes, Yaghootkar, Hanieh, Fairfax, Benjamin P., Andiappan, Anand Kumar, Li, Yang, Fu, Jingyuan, Karjalainen, Juha, Platteel, Mathieu, Visschedijk, Marijn, Weersma, Rinse K., Kasela, Silva, Milani, Lili, Tserel, Liina, Peterson, Pärt, Reinmaa, Eva, Hofman, Albert, Uitterlinden, André G., Rivadeneira, Fernando, Homuth, Georg, Petersmann, Astrid, Lorbeer, Roberto, Prokisch, Holger, Meitinger, Thomas, Herder, Christian, Roden, Michael, Grallert, Harald, Ripatti, Samuli, Perola, Markus, Wood, Andrew R., Melzer, David, Ferrucci, Luigi, Singleton, Andrew B., Hernandez, Dena G., Knight, Julian C., Melchiotti, Rossella, Lee, Bernett, Poidinger, Michael, Zolezzi, Francesca, Larbi, Anis, Wang, De Yun, van den Berg, Leonard H., Veldink, Jan H., Rotzschke, Olaf, Makino, Seiko, Salomaa, Veikko, Strauch, Konstantin, Völker, Uwe, van Meurs, Joyce B. J., Metspalu, Andres, Wijmenga, Cisca, Jansen, Ritsert C., and Franke, Lude

Abstract

The functional consequences of trait associated SNPs are often investigated using expression quantitative trait locus (eQTL) mapping. While trait-associated variants may operate in a cell-type specific manner, eQTL datasets for such cell-types may not always be available. We performed a genome-environment interaction (GxE) meta-analysis on data from 5,683 samples to infer the cell type specificity of whole blood cis-eQTLs. We demonstrate that this method is able to predict neutrophil and lymphocyte specific cis-eQTLs and replicate these predictions in independent cell-type specific datasets. Finally, we show that SNPs associated with Crohn’s disease preferentially affect gene expression within neutrophils, including the archetypal NOD2 locus.

Published
2015
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12. Haplotype Phasing and Inheritance of Copy Number Variants in Nuclear Families

Author

Palta, Priit, Kaplinski, Lauris, Nagirnaja, Liina, Veidenberg, Andres, Möls, Märt, Nelis, Mari, Esko, Tõnu, Metspalu, Andres, Laan, Maris, and Remm, Maido

Abstract

DNA copy number variants (CNVs) that alter the copy number of a particular DNA segment in the genome play an important role in human phenotypic variability and disease susceptibility. A number of CNVs overlapping with genes have been shown to confer risk to a variety of human diseases thus highlighting the relevance of addressing the variability of CNVs at a higher resolution. So far, it has not been possible to deterministically infer the allelic composition of different haplotypes present within the CNV regions. We have developed a novel computational method, called PiCNV, which enables to resolve the haplotype sequence composition within CNV regions in nuclear families based on SNP genotyping microarray data. The algorithm allows to i) phase normal and CNV-carrying haplotypes in the copy number variable regions, ii) resolve the allelic copies of rearranged DNA sequence within the haplotypes and iii) infer the heritability of identified haplotypes in trios or larger nuclear families. To our knowledge this is the first program available that can deterministically phase null, mono-, di-, tri- and tetraploid genotypes in CNV loci. We applied our method to study the composition and inheritance of haplotypes in CNV regions of 30 HapMap Yoruban trios and 34 Estonian families. For 93.6% of the CNV loci, PiCNV enabled to unambiguously phase normal and CNV-carrying haplotypes and follow their transmission in the corresponding families. Furthermore, allelic composition analysis identified the co-occurrence of alternative allelic copies within 66.7% of haplotypes carrying copy number gains. We also observed less frequent transmission of CNV-carrying haplotypes from parents to children compared to normal haplotypes and identified an emergence of several de novo deletions and duplications in the offspring.

Published
2015
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13. Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population

Author

Lim, Elaine T., Würtz, Peter, Havulinna, Aki S., Palta, Priit, Tukiainen, Taru, Rehnström, Karola, Esko, Tõnu, Mägi, Reedik, Inouye, Michael, Lappalainen, Tuuli, Chan, Yingleong, Salem, Rany M., Lek, Monkol, Flannick, Jason, Sim, Xueling, Manning, Alisa, Ladenvall, Claes, Bumpstead, Suzannah, Hämäläinen, Eija, Aalto, Kristiina, Maksimow, Mikael, Salmi, Marko, Blankenberg, Stefan, Ardissino, Diego, Shah, Svati, Horne, Benjamin, McPherson, Ruth, Hovingh, Gerald K., Reilly, Muredach P., Watkins, Hugh, Goel, Anuj, Farrall, Martin, Girelli, Domenico, Reiner, Alex P., Stitziel, Nathan O., Kathiresan, Sekar, Gabriel, Stacey, Barrett, Jeffrey C., Lehtimäki, Terho, Laakso, Markku, Groop, Leif, Kaprio, Jaakko, Perola, Markus, McCarthy, Mark I., Boehnke, Michael, Altshuler, David M., Lindgren, Cecilia M., Hirschhorn, Joel N., Metspalu, Andres, Freimer, Nelson B., Zeller, Tanja, Jalkanen, Sirpa, Koskinen, Seppo, Raitakari, Olli, Durbin, Richard, MacArthur, Daniel G., Salomaa, Veikko, Ripatti, Samuli, Daly, Mark J., and Palotie, Aarno

Subjects
Biology and Life Sciences, Computational Biology, Genome Analysis, Genome-Wide Association Studies, Evolutionary Biology, Population Genetics, Genetics, Genetics of Disease, Genetic Disorders, Heredity, Quantitative Traits, Human Genetics, Genetic Association Studies, Gene Disruption, Genomics, Phenotypes
Abstract

Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5–5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p<5×10−8) including splice variants in LPA that lowered plasma lipoprotein(a) levels (P = 1.5×10−117). Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR = 0.84, P = 3×10−4), demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health Registers.

Published
2014
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14. Novel Approach Identifies SNPs in SLC2A10 and KCNK9 with Evidence for Parent-of-Origin Effect on Body Mass Index

Author

Hoggart, Clive J., Venturini, Giulia, Mangino, Massimo, Gomez, Felicia, Ascari, Giulia, Zhao, Jing Hua, Teumer, Alexander, Winkler, Thomas W., Tšernikova, Natalia, Luan, Jian'an, Mihailov, Evelin, Ehret, Georg B., Zhang, Weihua, Lamparter, David, Esko, Tõnu, Macé, Aurelien, Rüeger, Sina, Bochud, Pierre-Yves, Barcella, Matteo, Dauvilliers, Yves, Benyamin, Beben, Evans, David M., Hayward, Caroline, Lopez, Mary F., Franke, Lude, Russo, Alessia, Heid, Iris M., Salvi, Erika, Vendantam, Sailaja, Arking, Dan E., Boerwinkle, Eric, Chambers, John C., Fiorito, Giovanni, Grallert, Harald, Guarrera, Simonetta, Homuth, Georg, Huffman, Jennifer E., Porteous, David, Moradpour, Darius, Iranzo, Alex, Hebebrand, Johannes, Kemp, John P., Lammers, Gert J., Aubert, Vincent, Heim, Markus H., Martin, Nicholas G., Montgomery, Grant W., Peraita-Adrados, Rosa, Santamaria, Joan, Negro, Francesco, Schmidt, Carsten O., Scott, Robert A., Spector, Tim D., Strauch, Konstantin, Völzke, Henry, Wareham, Nicholas J., Yuan, Wei, Bell, Jordana T., Chakravarti, Aravinda, Kooner, Jaspal S., Peters, Annette, Matullo, Giuseppe, Wallaschofski, Henri, Whitfield, John B., Paccaud, Fred, Vollenweider, Peter, Bergmann, Sven, Beckmann, Jacques S., Tafti, Mehdi, Hastie, Nicholas D., Cusi, Daniele, Bochud, Murielle, Frayling, Timothy M., Metspalu, Andres, Jarvelin, Marjo-Riitta, Scherag, André, Smith, George Davey, Borecki, Ingrid B., Rousson, Valentin, Hirschhorn, Joel N., Rivolta, Carlo, Loos, Ruth J. F., and Kutalik, Zoltán

Subjects
Physical Sciences, Mathematics, Statistics (Mathematics), Biostatistics, Statistical Methods, Biology and Life Sciences, Computational Biology, Genome Analysis, Genome-Wide Association Studies, Epigenomics, Developmental Biology, Genomic Imprinting, Genetics, Epigenetics, Genomics
Abstract

The phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present a novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. The method exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups. We applied the method to >56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six lead SNPs were carried forward for replication in five family-based studies (of ∼4,000 trios). Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (beta = 0.11 (SD), P<0.0027) compared to the respective maternal alleles. Real-time PCR experiments of lymphoblastoid cell lines from the CEPH families showed that expression of both genes was dependent on parental origin of the SNPs alleles (P<0.01). Our scheme opens new opportunities to exploit GWAS data of unrelated individuals to identify POEs and demonstrates that they play an important role in adult obesity.

Published
2014
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15. Biomarker Profiling by Nuclear Magnetic Resonance Spectroscopy for the Prediction of All-Cause Mortality: An Observational Study of 17,345 Persons

Author

Fischer, Krista, Kettunen, Johannes, Würtz, Peter, Haller, Toomas, Havulinna, Aki S., Kangas, Antti J., Soininen, Pasi, Esko, Tõnu, Tammesoo, Mari-Liis, Mägi, Reedik, Smit, Steven, Palotie, Aarno, Ripatti, Samuli, Salomaa, Veikko, Ala-Korpela, Mika, Perola, Markus, and Metspalu, Andres

Subjects
Biology, Biochemistry, Blood chemistry, Metabolism, Biotechnology, Medicine, Diagnostic medicine, Clinical laboratory sciences, Clinical chemistry, Epidemiology, Biomarker epidemiology, Epidemiology of aging, Molecular epidemiology, Public health, Preventive medicine
Abstract

Background: Early identification of ambulatory persons at high short-term risk of death could benefit targeted prevention. To identify biomarkers for all-cause mortality and enhance risk prediction, we conducted high-throughput profiling of blood specimens in two large population-based cohorts. Methods and Findings: 106 candidate biomarkers were quantified by nuclear magnetic resonance spectroscopy of non-fasting plasma samples from a random subset of the Estonian Biobank (n = 9,842; age range 18–103 y; 508 deaths during a median of 5.4 y of follow-up). Biomarkers for all-cause mortality were examined using stepwise proportional hazards models. Significant biomarkers were validated and incremental predictive utility assessed in a population-based cohort from Finland (n = 7,503; 176 deaths during 5 y of follow-up). Four circulating biomarkers predicted the risk of all-cause mortality among participants from the Estonian Biobank after adjusting for conventional risk factors: alpha-1-acid glycoprotein (hazard ratio [HR] 1.67 per 1–standard deviation increment, 95% CI 1.53–1.82, p = 5×10−31), albumin (HR 0.70, 95% CI 0.65–0.76, p = 2×10−18), very-low-density lipoprotein particle size (HR 0.69, 95% CI 0.62–0.77, p = 3×10−12), and citrate (HR 1.33, 95% CI 1.21–1.45, p = 5×10−10). All four biomarkers were predictive of cardiovascular mortality, as well as death from cancer and other nonvascular diseases. One in five participants in the Estonian Biobank cohort with a biomarker summary score within the highest percentile died during the first year of follow-up, indicating prominent systemic reflections of frailty. The biomarker associations all replicated in the Finnish validation cohort. Including the four biomarkers in a risk prediction score improved risk assessment for 5-y mortality (increase in C-statistics 0.031, p = 0.01; continuous reclassification improvement 26.3%, p = 0.001). Conclusions: Biomarker associations with cardiovascular, nonvascular, and cancer mortality suggest novel systemic connectivities across seemingly disparate morbidities. The biomarker profiling improved prediction of the short-term risk of death from all causes above established risk factors. Further investigations are needed to clarify the biological mechanisms and the utility of these biomarkers for guiding screening and prevention. Please see later in the article for the Editors' Summary

Published
2014
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16. Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

Author

Randall, Joshua C., Winkler, Thomas W., Kutalik, Zoltán, Berndt, Sonja I., Jackson, Anne U., Monda, Keri L., Kilpeläinen, Tuomas O., Esko, Tõnu, Mägi, Reedik, Li, Shengxu, Workalemahu, Tsegaselassie, Feitosa, Mary F., Croteau-Chonka, Damien C., Day, Felix R., Fall, Tove, Ferreira, Teresa, Gustafsson, Stefan, Locke, Adam E., Mathieson, Iain, Scherag, Andre, Vedantam, Sailaja, Wood, Andrew R., Liang, Liming, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Dermitzakis, Emmanouil T., Dimas, Antigone S., Karpe, Fredrik, Min, Josine L., Nicholson, George, Clegg, Deborah J., Person, Thomas, Krohn, Jon P., Bauer, Sabrina, Buechler, Christa, Eisinger, Kristina, Bonnefond, Amélie, Froguel, Philippe, Hottenga, Jouke-Jan, Prokopenko, Inga, Waite, Lindsay L., Harris, Tamara B., Smith, Albert Vernon, Shuldiner, Alan R., McArdle, Wendy L., Caulfield, Mark J., Munroe, Patricia B., Grönberg, Henrik, Chen, Yii-Der Ida, Li, Guo, Beckmann, Jacques S., Johnson, Toby, Thorsteinsdottir, Unnur, Teder-Laving, Maris, Khaw, Kay-Tee, Wareham, Nicholas J., Zhao, Jing Hua, Amin, Najaf, Oostra, Ben A., Kraja, Aldi T., Province, Michael A., Cupples, L. Adrienne, Heard-Costa, Nancy L., Kaprio, Jaakko, Ripatti, Samuli, Surakka, Ida, Collins, Francis S., Saramies, Jouko, Tuomilehto, Jaakko, Jula, Antti, Salomaa, Veikko, Erdmann, Jeanette, Hengstenberg, Christian, Loley, Christina, Schunkert, Heribert, Lamina, Claudia, Wichmann, H. Erich, Albrecht, Eva, Gieger, Christian, Hicks, Andrew A., Johansson, Åsa, Pramstaller, Peter P., Kathiresan, Sekar, Speliotes, Elizabeth K., Penninx, Brenda, Hartikainen, Anna-Liisa, Jarvelin, Marjo-Riitta, Gyllensten, Ulf, Boomsma, Dorret I., Campbell, Harry, Wilson, James F., Chanock, Stephen J., Farrall, Martin, Goel, Anuj, Medina-Gomez, Carolina, Rivadeneira, Fernando, Estrada, Karol, Uitterlinden, André G., Hofman, Albert, Zillikens, M. Carola, den Heijer, Martin, Kiemeney, Lambertus A., Maschio, Andrea, Hall, Per, Tyrer, Jonathan, Teumer, Alexander, Völzke, Henry, Kovacs, Peter, Tönjes, Anke, Mangino, Massimo, Spector, Tim D., Hayward, Caroline, Rudan, Igor, Hall, Alistair S., Samani, Nilesh J., Attwood, Antony Paul, Sambrook, Jennifer G., Hung, Joseph, Palmer, Lyle J., Lokki, Marja-Liisa, Sinisalo, Juha, Boucher, Gabrielle, Huikuri, Heikki, Lorentzon, Mattias, Ohlsson, Claes, Eklund, Niina, Eriksson, Johan G., Barlassina, Cristina, Rivolta, Carlo, Nolte, Ilja M., Snieder, Harold, Van der Klauw, Melanie M., Van Vliet-Ostaptchouk, Jana V., Gejman, Pablo V., Shi, Jianxin, Jacobs, Kevin B., Wang, Zhaoming, Bakker, Stephan J. L., Mateo Leach, Irene, Navis, Gerjan, van der Harst, Pim, Martin, Nicholas G., Medland, Sarah E., Montgomery, Grant W., Yang, Jian, Chasman, Daniel I., Ridker, Paul M., Rose, Lynda M., Lehtimäki, Terho, Raitakari, Olli, Absher, Devin, Iribarren, Carlos, Basart, Hanneke, Hovingh, Kees G., Hyppönen, Elina, Power, Chris, Anderson, Denise, Beilby, John P., Hui, Jennie, Jolley, Jennifer, Sager, Hendrik, Bornstein, Stefan R., Schwarz, Peter E. H., Kristiansson, Kati, Perola, Markus, Lindström, Jaana, Swift, Amy J., Uusitupa, Matti, Atalay, Mustafa, Lakka, Timo A., Rauramaa, Rainer, Bolton, Jennifer L., Fowkes, Gerry, Fraser, Ross M., Price, Jackie F., Fischer, Krista, KrjutÅ¡kov, Kaarel, Metspalu, Andres, Mihailov, Evelin, Langenberg, Claudia, Luan, Jian'an, Ong, Ken K., Chines, Peter S., Keinanen-Kiukaanniemi, Sirkka M., Saaristo, Timo E., Edkins, Sarah, Franks, Paul W., Hallmans, Göran, Shungin, Dmitry, Morris, Andrew David, Palmer, Colin N. A., Erbel, Raimund, Moebus, Susanne, Nöthen, Markus M., Pechlivanis, Sonali, Hveem, Kristian, Narisu, Narisu, Hamsten, Anders, Humphries, Steve E., Strawbridge, Rona J., Tremoli, Elena, Grallert, Harald, Thorand, Barbara, Illig, Thomas, Koenig, Wolfgang, Müller-Nurasyid, Martina, Peters, Annette, Boehm, Bernhard O., Kleber, Marcus E., März, Winfried, Winkelmann, Bernhard R., Kuusisto, Johanna, Laakso, Markku, Arveiler, Dominique, Cesana, Giancarlo, Kuulasmaa, Kari, Virtamo, Jarmo, Yarnell, John W. G., Kuh, Diana, Wong, Andrew, Lind, Lars, de Faire, Ulf, Gigante, Bruna, Magnusson, Patrik K. E., Pedersen, Nancy L., Dedoussis, George, Dimitriou, Maria, Kolovou, Genovefa, Kanoni, Stavroula, Stirrups, Kathleen, Bonnycastle, Lori L., Njølstad, Inger, Wilsgaard, Tom, Ganna, Andrea, Rehnberg, Emil, Hingorani, Aroon, Kivimaki, Mika, Kumari, Meena, Assimes, Themistocles L., Barroso, Inês, Boehnke, Michael, Borecki, Ingrid B., Deloukas, Panos, Fox, Caroline S., Frayling, Timothy, Groop, Leif C., Haritunians, Talin, Hunter, David, Ingelsson, Erik, Kaplan, Robert, Mohlke, Karen L., O'Connell, Jeffrey R., Schlessinger, David, Strachan, David P., Stefansson, Kari, van Duijn, Cornelia M., Abecasis, Gonçalo R., McCarthy, Mark I., Hirschhorn, Joel N., Qi, Lu, Loos, Ruth J. F., Lindgren, Cecilia M., North, Kari E., and Heid, Iris M.

Subjects
Medicine, Epidemiology, Genetic Epidemiology
Abstract

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10−8), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

Published
2013
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17. Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function

Author

Pattaro, Cristian, Köttgen, Anna, Teumer, Alexander, Böger, Carsten A., Fuchsberger, Christian, Olden, Matthias, Chen, Ming-Huei, Tin, Adrienne, Taliun, Daniel, Li, Man, Gao, Xiaoyi, Gorski, Mathias, Yang, Qiong, Hundertmark, Claudia, Foster, Meredith C., Glazer, Nicole, Isaacs, Aaron, Liu, Ching-Ti, Smith, Albert V., O'Connell, Jeffrey R., Struchalin, Maksim, Tanaka, Toshiko, Gierman, Hinco J., Feitosa, Mary, Hwang, Shih-Jen, Atkinson, Elizabeth J., Lohman, Kurt, Johansson, Åsa, Tönjes, Anke, Dehghan, Abbas, Chouraki, Vincent, Holliday, Elizabeth G., Sorice, Rossella, Kutalik, Zoltan, Lehtimäki, Terho, Esko, Tõnu, Deshmukh, Harshal, Ulivi, Sheila, Murgia, Federico, Trompet, Stella, Imboden, Medea, Kollerits, Barbara, Pistis, Giorgio, Harris, Tamara B., Launer, Lenore J., Aspelund, Thor, Eiriksdottir, Gudny, Mitchell, Braxton D., Boerwinkle, Eric, Schmidt, Helena, Cavalieri, Margherita, Rao, Madhumathi, Demirkan, Ayse, Oostra, Ben A., de Andrade, Mariza, Ding, Jingzhong, Andrews, Jeanette S., Freedman, Barry I., Koenig, Wolfgang, Illig, Thomas, Döring, Angela, Wichmann, H.-Erich, Kolcic, Ivana, Zemunik, Tatijana, Boban, Mladen, Minelli, Cosetta, Wheeler, Heather E., Igl, Wilmar, Zaboli, Ghazal, Wild, Sarah H., Wright, Alan F., Campbell, Harry, Ellinghaus, David, Nöthlings, Ute, Jacobs, Gunnar, Biffar, Reiner, Endlich, Karlhans, Ernst, Florian, Homuth, Georg, Kroemer, Heyo K., Nauck, Matthias, Stracke, Sylvia, Völker, Uwe, Völzke, Henry, Kovacs, Peter, Stumvoll, Michael, Mägi, Reedik, Uitterlinden, Andre G., Rivadeneira, Fernando, Aulchenko, Yurii S., Polasek, Ozren, Hastie, Nick, Vitart, Veronique, Helmer, Catherine, Wang, Jie Jin, Ruggiero, Daniela, Bergmann, Sven, Kähönen, Mika, Viikari, Jorma, Nikopensius, Tiit, Province, Michael, Ketkar, Shamika, Colhoun, Helen, Doney, Alex, Robino, Antonietta, Giulianini, Franco, Krämer, Bernhard K., Portas, Laura, Ford, Ian, Buckley, Brendan M., Adam, Martin, Thun, Gian-Andri, Paulweber, Bernhard, Haun, Margot, Sala, Cinzia, Metzger, Marie, Mitchell, Paul, Ciullo, Marina, Kim, Stuart K., Vollenweider, Peter, Raitakari, Olli, Metspalu, Andres, Palmer, Colin, Gasparini, Paolo, Pirastu, Mario, Jukema, J. Wouter, Probst-Hensch, Nicole M., Kronenberg, Florian, Toniolo, Daniela, Gudnason, Vilmundur, Shuldiner, Alan R., Coresh, Josef, Schmidt, Reinhold, Ferrucci, Luigi, Siscovick, David S., van Duijn, Cornelia M., Borecki, Ingrid, Kardia, Sharon L. R., Liu, Yongmei, Rudan, Igor, Gyllensten, Ulf, Wilson, James F., Franke, Andre, Pramstaller, Peter P., Rettig, Rainer, Prokopenko, Inga, Witteman, Jacqueline C. M., Hayward, Caroline, Parsa, Afshin, Bochud, Murielle, Heid, Iris M., Garnaas, Maija, O'Seaghdha, Conall, Li, Guo, Johnson, Andrew D., Cornelis, Marilyn, Chu, Audrey Yu-lei, Hu, Frank B., Turner, Stephen T., Hofman, Albert, Curhan, Gary Craig, Ridker, Paul M., Goessling, Wolfram, Chasman, Daniel Ian, Kao, W. H. Linda, and Fox, Caroline

Subjects
biology, genetics
Abstract

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near \(MPPED2\), \(DDX1\), \(SLC47A1\), \(CDK12\), \(CASP9\), and \(INO80\). Morpholino knockdown of \(mpped2\) and \(casp9\) in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

Published
2012
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