Browsing by Subject "CELL-TYPES"

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  • Knight, Anna K.; Craig, Jeffrey M.; Theda, Christiane; Baekvad-Hansen, Marie; Bybjerg-Grauholm, Jonas; Hansen, Christine S.; Hollegaard, Mads V.; Hougaard, David M.; Mortensen, Preben B.; Weinsheimer, Shantel M.; Werge, Thomas M.; Brennan, Patricia A.; Cubells, Joseph F.; Newport, D. Jeffrey; Stowe, Zachary N.; Cheong, Jeanie L. Y.; Dalach, Philippa; Doyle, Lex W.; Loke, Yuk J.; Baccarelli, Andrea A.; Just, Allan C.; Wright, Robert O.; Tellez-Rojo, Mara M.; Svensson, Katherine; Trevisi, Letizia; Kennedy, Elizabeth M.; Binder, Elisabeth B.; Iurato, Stella; Räikkönen, Katri; Lahti, Jari M. T.; Pesonen, Anu-Katriina; Kajantie, Eero; Villa, Pia M.; Laivuori, Hannele; Hämäläinen, Esa; Park, Hea Jin; Bailey, Lynn B.; Parets, Sasha E.; Kilaru, Varun; Menon, Ramkumar; Horvath, Steve; Bush, Nicole R.; LeWinn, Kaja Z.; Tylavsky, Frances A.; Conneely, Karen N.; Smith, Alicia K. (2016)
    Background: Gestational age is often used as a proxy for developmental maturity by clinicians and researchers alike. DNA methylation has previously been shown to be associated with age and has been used to accurately estimate chronological age in children and adults. In the current study, we examine whether DNA methylation in cord blood can be used to estimate gestational age at birth. Results: We find that gestational age can be accurately estimated from DNA methylation of neonatal cord blood and blood spot samples. We calculate a DNA methylation gestational age using 148 CpG sites selected through elastic net regression in six training datasets. We evaluate predictive accuracy in nine testing datasets and find that the accuracy of the DNA methylation gestational age is consistent with that of gestational age estimates based on established methods, such as ultrasound. We also find that an increased DNA methylation gestational age relative to clinical gestational age is associated with birthweight independent of gestational age, sex, and ancestry. Conclusions: DNA methylation can be used to accurately estimate gestational age at or near birth and may provide additional information relevant to developmental stage. Further studies of this predictor are warranted to determine its utility in clinical settings and for research purposes. When clinical estimates are available this measure may increase accuracy in the testing of hypotheses related to developmental age and other early life circumstances.
  • Hannon, Eilis; Dempster, Emma; Viana, Joana; Burrage, Joe; Smith, Adam R.; Macdonald, Ruby; St Clair, David; Mustard, Colette; Breen, Gerome; Therman, Sebastian; Kaprio, Jaakko; Toulopoulou, Timothea; Pol, Hilleke E. Hulshoff; Bohlken, Marc M.; Kahn, Rene S.; Nenadic, Igor; Hultman, Christina M.; Murray, Robin M.; Collier, David A.; Bass, Nick; Gurling, Hugh; McQuillin, Andrew; Schalkwyk, Leonard; Mill, Jonathan (2016)
    Background: Schizophrenia is a highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated. Results: We performed a multi-stage epigenome-wide association study, quantifying genome-wide patterns of DNA methylation in a total of 1714 individuals from three independent sample cohorts. We have identified multiple differentially methylated positions and regions consistently associated with schizophrenia across the three cohorts; these effects are independent of important confounders such as smoking. We also show that epigenetic variation at multiple loci across the genome contributes to the polygenic nature of schizophrenia. Finally, we show how DNA methylation quantitative trait loci in combination with Bayesian co-localization analyses can be used to annotate extended genomic regions nominated by studies of schizophrenia, and to identify potential regulatory variation causally involved in disease. Conclusions: This study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological approach that can be used to inform epigenome-wide association study analyses of other complex traits and diseases. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with etiological variation, and of using DNA methylation quantitative trait loci to refine the functional and regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation.
  • Girchenko, Polina; Lahti, Jari; Czamara, Darina; Knight, Anna K.; Jones, Meaghan J.; Suarez Figueiredo, Anna; Hämäläinen, Esa; Kajantie, Eero; Laivuori, Hannele; Villa, Pia M.; Reynolds, Rebecca M.; Kobor, Michael S.; Smith, Alicia K.; Binder, Elisabeth B.; Räikkönen, Katri (2017)
    Background: A recent study has shown that it is possible to accurately estimate gestational age (GA) at birth from the DNA methylation (DNAm) of fetal umbilical cord blood/newborn blood spots. This DNAm GA predictor may provide additional information relevant to developmental stage. In 814 mother-neonate pairs, we evaluated the associations between DNAm GA and a number of maternal and offspring characteristics. These characteristics reflect prenatal environmental adversity and are expected to influence newborn developmental stage. Results: DNAm GA acceleration (GAA; i.e., older DNAm GA than chronological GA) of the offspring at birth was associated with maternal age of over 40 years at delivery, pre-eclampsia and fetal demise in a previous pregnancy, maternal pre-eclampsia and treatment with antenatal betamethasone in the index pregnancy, lower neonatal birth size, lower 1-min Apgar score, and female sex. DNAm GA deceleration (GAD; i.e., younger DNAm GA than chronological GA) of the offspring at birth was associated with insulin-treated gestational diabetes mellitus (GDM) in a previous pregnancy and Sjogren's syndrome. These findings were more accentuated when the DNAm GA calculation was based on the raw difference between DNAm GA and GA than on the residual from the linear regression of DNAm GA on GA. Conclusions: Our findings show that variations in the DNAm GA of the offspring at birth are associated with a number of maternal and offspring characteristics known to reflect exposure to prenatal environmental adversity. Future studies should be aimed at determining if this biological variation is predictive of developmental adversity.
  • Tammimies, Kristiina; Bieder, Andrea; Lauter, Gilbert; Sugiaman-Trapman, Debora; Torchet, Rachel; Hokkanen, Marie-Estelle; Burghoorn, Jan; Castrén, Eero; Kere, Juha; Tapia-Paez, Isabel; Swoboda, Peter (2016)
    DYX1C1, DCDC2, and KIAA0319 are three of the most replicated dyslexia candidate genes (DCGs). Recently, these DCGs were implicated in functions at the cilium. Here, we investigate the regulation of these DCGs by Regulatory Factor X transcription factors (RFX TFs), a gene family known for transcriptionally regulating ciliary genes. We identify conserved X-box motifs in the promoter regions of DYX1C1, DCDC2, and KIAA0319 and demonstrate their functionality, as well as the ability to recruit RFX TFs using reporter gene and electrophoretic mobility shift assays. Furthermore, we uncover a complex regulation pattern between RFX1, RFX2, and RFX3 and their significant effect on modifying the endogenous expression of DYX1C1 and DCDC2 in a human retinal pigmented epithelial cell line immortalized with hTERT (hTERT-RPE1). In addition, induction of ciliogenesis increases the expression of RFX TFs and DCGs. At the protein level, we show that endogenous DYX1C1 localizes to the base of the cilium, whereas DCDC2 localizes along the entire axoneme of the cilium, thereby validating earlier localization studies using overexpression models. Our results corroborate the emerging role of DCGs in ciliary function and characterize functional noncoding elements, X-box promoter motifs, in DCG promoter regions, which thus can be targeted for mutation screening in dyslexia and ciliopathies associated with these genes.
  • Jiang, Xia; O'Reilly, Paul F.; Aschard, Hugues; Hsu, Yi-Hsiang; Richards, J. Brent; Dupuis, Josee; Ingelsson, Erik; Karasik, David; Pilz, Stefan; Berry, Diane; Kestenbaum, Bryan; Zheng, Jusheng; Luan, Jianan; Sofianopoulou, Eleni; Streeten, Elizabeth A.; Albanes, Demetrius; Lutsey, Pamela L.; Yao, Lu; Tang, Weihong; Econs, Michael J.; Wallaschofski, Henri; Voelzke, Henry; Zhou, Ang; Power, Chris; McCarthy, Mark I.; Michos, Erin D.; Boerwinkle, Eric; Weinstein, Stephanie J.; Freedman, Neal D.; Huang, Wen-Yi; Van Schoor, Natasja M.; van der Velde, Nathalie; de Groot, Lisette C. P. G. M.; Enneman, Anke; Cupples, L. Adrienne; Booth, Sarah L.; Vasan, Ramachandran S.; Liu, Ching-Ti; Zhou, Yanhua; Ripatti, Samuli; Ohlsson, Claes; Vandenput, Liesbeth; Lorentzon, Mattias; Eriksson, Johan G.; Shea, M. Kyla; Houston, Denise K.; Kritchevsky, Stephen B.; Liu, Yongmei; Lohman, Kurt K.; Ferrucci, Luigi; Peacock, Munro; Gieger, Christian; Beekman, Marian; Slagboom, Eline; Deelen, Joris; van Heemst, Diana; Kleber, Marcus E.; Maerz, Winfried; de Boer, Ian H.; Wood, Alexis C.; Rotter, Jerome I.; Rich, Stephen S.; Robinson-Cohen, Cassianne; den Heijer, Martin; Jarvelin, Marjo-Riitta; Cavadino, Alana; Joshi, Peter K.; Wilson, James F.; Hayward, Caroline; Lind, Lars; Michaelsson, Karl; Trompet, Stella; Zillikens, M. Carola; Uitterlinden, Andre G.; Rivadeneira, Fernando; Broer, Linda; Zgaga, Lina; Campbell, Harry; Theodoratou, Evropi; Farrington, Susan M.; Timofeeva, Maria; Dunlop, Malcolm G.; Valdes, Ana M.; Tikkanen, Emmi; Lehtimaki, Terho; Lyytikainen, Leo-Pekka; Kahonen, Mika; Raitakari, Olli T.; Mikkila, Vera; Ikram, M. Arfan; Sattar, Naveed; Jukema, J. Wouter; Wareham, Nicholas J.; Langenberg, Claudia; Forouhi, Nita G.; Gundersen, Thomas E.; Khaw, Kay-Tee; Butterworth, Adam S.; Danesh, John; Spector, Timothy; Wang, Thomas J.; Hypponen, Elina; Kraft, Peter; Kiel, Douglas P. (2018)
    Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7x10(-9) at rs8018720 in SEC23A, and P = 1.9x10(-14) at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
  • Jiang, Xia; Finucane, Hilary K.; Schumacher, Fredrick R.; Schmit, Stephanie L.; Tyrer, Jonathan P.; Han, Younghun; Michailidou, Kyriaki; Lesseur, Corina; Kuchenbaecker, Karoline B.; Dennis, Joe; Conti, David V.; Casey, Graham; Gaudet, Mia M.; Huyghe, Jeroen R.; Albanes, Demetrius; Aldrich, Melinda C.; Andrew, Angeline S.; Andrulis, Irene L.; Anton-Culver, Hoda; Antoniou, Antonis C.; Antonenkova, Natalia N.; Arnold, Susanne M.; Aronson, Kristan J.; Arun, Banu K.; Bandera, Elisa V.; Barkardottir, Rosa B.; Barnes, Daniel R.; Batra, Jyotsna; Beckmann, Matthias W.; Benitez, Javier; Benlloch, Sara; Berchuck, Andrew; Berndt, Sonja I.; Bickeboeller, Heike; Bien, Stephanie A.; Blomqvist, Carl; Boccia, Stefania; Bogdanova, Natalia V.; Bojesen, Stig E.; Bolla, Manjeet K.; Brauch, Hiltrud; Brenner, Hermann; Brenton, James D.; Brook, Mark N.; Brunet, Joan; Brunnstrom, Hans; Buchanan, Daniel D.; Burwinkel, Barbara; Butzow, Ralf; Cadoni, Gabriella; Caldes, Trinidad; Caligo, Maria A.; Campbell, Ian; Campbell, Peter T.; Cancel-Tassin, Geraldine; Cannon-Albright, Lisa; Campa, Daniele; Caporaso, Neil; Carvalho, Andre L.; Chan, Andrew T.; Chang-Claude, Jenny; Chanock, Stephen J.; Chen, Chu; Christiani, David C.; Claes, Kathleen B. M.; Claessens, Frank; Clements, Judith; Collee, J. Margriet; Correa, Marcia Cruz; Couch, Fergus J.; Cox, Angela; Cunningham, Julie M.; Cybulski, Cezary; Czene, Kamila; Daly, Mary B.; defazio, Anna; Devilee, Peter; Diez, Orland; Gago-Dominguez, Manuela; Donovan, Jenny L.; Doerk, Thilo; Duell, Eric J.; Dunning, Alison M.; Dwek, Miriam; Eccles, Diana M.; Edlund, Christopher K.; Edwards, Digna R. Velez; Ellberg, Carolina; Evans, D. Gareth; Fasching, Peter A.; Ferris, Robert L.; Liloglou, Triantafillos; Figueiredo, Jane C.; Fletcher, Olivia; Fortner, Renee T.; Fostira, Florentia; Franceschi, Silvia; Friedman, Eitan; Gallinger, Steven J.; Ganz, Patricia A.; Garber, Judy; Garcia-Saenz, Jose A.; Gayther, Simon A.; Giles, Graham G.; Godwin, Andrew K.; Goldberg, Mark S.; Goldgar, David E.; Goode, Ellen L.; Goodman, Marc T.; Goodman, Gary; Grankvist, Kjell; Greene, Mark H.; Gronberg, Henrik; Gronwald, Jacek; Guenel, Pascal; Hakansson, Niclas; Hall, Per; Hamann, Ute; Hamdy, Freddie C.; Hamilton, Robert J.; Hampe, Jochen; Haugen, Aage; Heitz, Florian; Herrero, Rolando; Hillemanns, Peter; Hoffmeister, Michael; Hogdall, Estrid; Hong, Yun-Chul; Hopper, John L.; Houlston, Richard; Hulick, Peter J.; Hunter, David J.; Huntsman, David G.; Idos, Gregory; Imyanitov, Evgeny N.; Ingles, Sue Ann; Isaacs, Claudine; Jakubowska, Anna; James, Paul; Jenkins, Mark A.; Johansson, Mattias; Johansson, Mikael; John, Esther M.; Joshi, Amit D.; Kaneva, Radka; Karlan, Beth Y.; Kelemen, Linda E.; Kuhl, Tabea; Khaw, Kay-Tee; Khusnutdinova, Elza; Kibel, Adam S.; Kiemeney, Lambertus A.; Kim, Jeri; Kjaer, Susanne K.; Knight, Julia A.; Kogevinas, Manolis; Kote-Jarai, Zsofia; Koutros, Stella; Kristensen, Vessela N.; Kupryjanczyk, Jolanta; Lacko, Martin; Lam, Stephan; Lambrechts, Diether; Landi, Maria Teresa; Lazarus, Philip; Le, Nhu D.; Lee, Eunjung; Lejbkowicz, Flavio; Lenz, Heinz-Josef; Leslie, Goska; Lessel, Davor; Lester, Jenny; Levine, Douglas A.; Li, Li; Li, Christopher I.; Lindblom, Annika; Lindor, Noralane M.; Liu, Geoffrey; Loupakis, Fotios; Lubinski, Jan; Maehle, Lovise; Maier, Christiane; Mannermaa, Arto; Le Marchand, Loic; Margolin, Sara; May, Taymaa; McGuffog, Lesley; Meindl, Alfons; Middha, Pooja; Miller, Austin; Milne, Roger L.; MacInnis, Robert J.; Modugno, Francesmary; Montagna, Marco; Moreno, Victor; Moysich, Kirsten B.; Mucci, Lorelei; Muir, Kenneth; Mulligan, Anna Marie; Nathanson, Katherine L.; Neal, David E.; Ness, Andrew R.; Neuhausen, Susan L.; Nevanlinna, Heli; Newcomb, Polly A.; Newcomb, Lisa F.; Nielsen, Finn Cilius; Nikitina-Zake, Liene; Nordestgaard, Borge G.; Nussbaum, Robert L.; Offit, Kenneth; Olah, Edith; Al Olama, Ali Amin; Olopade, Olufunmilayo I.; Olshan, Andrew F.; Olsson, Hakan; Osorio, Ana; Pandha, Hardev; Park, Jong Y.; Pashayan, Nora; Parsons, Michael T.; Pejovic, Tanja; Penney, Kathryn L.; Peters, Wilbert H. M.; Phelan, Catherine M.; Phipps, Amanda I.; Plaseska-Karanfilska, Dijana; Pring, Miranda; Prokofyeva, Darya; Radice, Paolo; Stefansson, Kari; Ramus, Susan J.; Raskin, Leon; Rennert, Gad; Rennert, Hedy S.; van Rensburg, Elizabeth J.; Riggan, Marjorie J.; Risch, Harvey A.; Risch, Angela; Roobol, Monique J.; Rosenstein, Barry S.; Rossing, Mary Anne; De Ruyck, Kim; Saloustros, Emmanouil; Sandler, Dale P.; Sawyer, Elinor J.; Schabath, Matthew B.; Schleutker, Johanna; Schmidt, Marjanka K.; Setiawan, V. Wendy; Shen, Hongbing; Siegel, Erin M.; Sieh, Weiva; Singer, Christian F.; Slattery, Martha L.; Sorensen, Karina Dalsgaard; Southey, Melissa C.; Spurdle, Amanda B.; Stanford, Janet L.; Stevens, Victoria L.; Stintzing, Sebastian; Stone, Jennifer; Sundfeldt, Karin; Sutphen, Rebecca; Swerdlow, Anthony J.; Tajara, Eloiza H.; Tangen, Catherine M.; Tardon, Adonina; Taylor, Jack A.; Teare, M. Dawn; Teixeira, Manuel R.; Terry, Mary Beth; Terry, Kathryn L.; Thibodeau, Stephen N.; Thomassen, Mads; Bjorge, Line; Tischkowitz, Marc; Toland, Amanda E.; Torres, Diana; Townsend, Paul A.; Travis, Ruth C.; Tung, Nadine; Tworoger, Shelley S.; Ulrich, Cornelia M.; Usmani, Nawaid; Vachon, Celine M.; Van Nieuwenhuysen, Els; Vega, Ana; Aguado-Barrera, Miguel Elias; Wang, Qin; Webb, Penelope M.; Weinberg, Clarice R.; Weinstein, Stephanie; Weissler, Mark C.; Weitzel, Jeffrey N.; West, Catharine M. L.; White, Emily; Whittemore, Alice S.; Wichmann, H-Erich; Wiklund, Fredrik; Winqvist, Robert; Wolk, Alicja; Woll, Penella; Woods, Michael; Wu, Anna H.; Wu, Xifeng; Yannoukakos, Drakoulis; Zheng, Wei; Zienolddiny, Shanbeh; Ziogas, Argyrios; Zorn, Kristin K.; Lane, Jacqueline M.; Saxena, Richa; Thomas, Duncan; Hung, Rayjean J.; Diergaarde, Brenda; Mckay, James; Peters, Ulrike; Hsu, Li; Garcia-Closas, Montserrat; Eeles, Rosalind A.; Chenevix-Trench, Georgia; Brennan, Paul J.; Haiman, Christopher A.; Simard, Jacques; Easton, Douglas F.; Gruber, Stephen B.; Pharoah, Paul D. P.; Price, Alkes L.; Pasaniuc, Bogdan; Amos, Christopher I.; Kraft, Peter; Lindstrom, Sara (2019)
    Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
  • Suarez, Anna; Lahti, Jari; Czamara, Darina; Lahti-Pulkkinen, Marius; Knight, Anna K.; Girchenko, Polina; Hämäläinen, Esa; Kajantie, Eero; Lipsanen, Jari; Laivuori, Hannele; Villa, Pia M.; Reynolds, Rebecca M.; Smith, Alicia K.; Binder, Elisabeth B.; Räikkönen, Katri (2018)
    Objective: Maternal antenatal depression may compromise the fetal developmental milieu and contribute to individual differences in aging and disease trajectories in later life. We evaluated the association between maternal antenatal depression and a novel biomarker of aging at birth, namely epigenetic gestational age (GA) based on fetal cord blood methylation data. We also examined whether this biomarker prospectively predicts and mediates maternal effects on early childhood psychiatric problems. Method: A total of 694 mothers from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) Study provided information on history of depression diagnosed before pregnancy; 581 completed the Center for Epidemiological Studies Depression Scale throughout pregnancy, and 407 completed the Child Behavior Checklist at child's age 3.7 years (SD = 0.75 year). DNA methylation (DNAm) GA of fetal cord blood DNA was based on the methylation profile of 148 selected cytosine linked to guanine by phosphate (CpG) sites. Epigenetic GA was calculated as the arithmetic difference between DNAm GA and chronological GA and adjusted for chronological GA. Results: Maternal history of depression diagnosed before pregnancy (mean difference = -0.25 SD units, 95% CI = -0.46 to -0.03) and greater antenatal depressive symptoms (-0.08 SD unit per I-SD unit increase, 95% CI = -0.16 to -0.004) were associated with child's lower epigenetic GA. Child's lower epigenetic GA, in turn, prospectively predicted total and internalizing problems and partially mediated the effects of maternal antenatal depression on internalizing problems in boys. Conclusion: Maternal antenatal depression is associated with lower epigenetic GA in offspring. This lower epigenetic GA seems to be associated with a developmental disadvantage for boys, who, in early childhood, show greater psychiatric problems.