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1. DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases

Author

Wielscher, Matthias, Mandaviya, Pooja R, Kuehnel, Brigitte, Joehanes, Roby, Mustafa, Rima, Robinson, Oliver, Zhang, Yan, Bodinier, Barbara, Walton, Esther, Mishra, Pashupati P, Schlosser, Pascal, Wilson, Rory, Tsai, Pei-Chien, Palaniswamy, Saranya, Marioni, Riccardo E, Fiorito, Giovanni, Cugliari, Giovanni, Karhunen, Ville, Ghanbari, Mohsen, Psaty, Bruce M, Loh, Marie, Bis, Joshua C, Lehne, Benjamin, Sotoodehnia, Nona, Deary, Ian J, Chadeau-Hyam, Marc, Brody, Jennifer A, Cardona, Alexia, Selvin, Elizabeth, Smith, Alicia K, Miller, Andrew H, Torres, Mylin A, Marouli, Eirini, Gào, Xin, Van Meurs, Joyce BJ, Graf-Schindler, Johanna, Rathmann, Wolfgang, Koenig, Wolfgang, Peters, Annette, Weninger, Wolfgang, Farlik, Matthias, Zhang, Tao, Chen, Wei, Xia, Yujing, Teumer, Alexander, Nauck, Matthias, Grabe, Hans J, Doerr, Macus, Lehtimäki, Terho, Guan, Weihua, Milani, Lili, Tanaka, Toshiko, Fisher, Krista, Waite, Lindsay L, Kasela, Silva, Vineis, Paolo, Verweij, Niek, Van Der Harst, Pim, Iacoviello, Licia, Sacerdote, Carlotta, Panico, Salvatore, Krogh, Vittorio, Tumino, Rosario, Tzala, Evangelia, Matullo, Giuseppe, Hurme, Mikko A, Raitakari, Olli T, Colicino, Elena, Baccarelli, Andrea A, Kähönen, Mika, Herzig, Karl-Heinz, Li, Shengxu, BIOS Consortium, Conneely, Karen N, Kooner, Jaspal S, Köttgen, Anna, Heijmans, Bastiaan T, Deloukas, Panos, Relton, Caroline, Ong, Ken K, Bell, Jordana T, Boerwinkle, Eric, Elliott, Paul, Brenner, Hermann, Beekman, Marian, Levy, Daniel, Waldenberger, Melanie, Chambers, John C, Dehghan, Abbas, Järvelin, Marjo-Riitta, Wielscher, Matthias [0000-0003-4138-1383], Mustafa, Rima [0000-0003-2623-5337], Robinson, Oliver [0000-0002-4735-0468], Bodinier, Barbara [0000-0002-0781-3624], Walton, Esther [0000-0002-0935-2200], Schlosser, Pascal [0000-0002-8460-0462], Wilson, Rory [0000-0001-6135-3764], Palaniswamy, Saranya [0000-0003-4145-540X], Karhunen, Ville [0000-0001-6064-1588], Ghanbari, Mohsen [0000-0002-9476-7143], Psaty, Bruce M [0000-0002-7278-2190], Loh, Marie [0000-0003-3626-8466], Bis, Joshua C [0000-0002-3409-1110], Chadeau-Hyam, Marc [0000-0001-8341-5436], Brody, Jennifer A [0000-0001-8509-148X], Cardona, Alexia [0000-0002-7877-5565], Smith, Alicia K [0000-0002-8537-5156], Miller, Andrew H [0000-0001-8260-7997], Marouli, Eirini [0000-0001-6179-1609], Gào, Xin [0000-0003-0108-6961], Koenig, Wolfgang [0000-0002-2064-9603], Peters, Annette [0000-0001-6645-0985], Farlik, Matthias [0000-0003-0698-2992], Chen, Wei [0000-0003-1566-7943], Xia, Yujing [0000-0003-0850-5591], Teumer, Alexander [0000-0002-8309-094X], Nauck, Matthias [0000-0002-6678-7964], Doerr, Macus [0000-0001-7471-475X], Lehtimäki, Terho [0000-0002-2555-4427], Milani, Lili [0000-0002-5323-3102], Fisher, Krista [0000-0002-3521-0599], van der Harst, Pim [0000-0002-2713-686X], Krogh, Vittorio [0000-0003-0122-8624], Herzig, Karl-Heinz [0000-0003-4460-2604], Li, Shengxu [0000-0001-9210-7283], Köttgen, Anna [0000-0002-4671-3714], Heijmans, Bastiaan T [0000-0001-5918-0534], Deloukas, Panos [0000-0001-9251-070X], Ong, Ken K [0000-0003-4689-7530], Bell, Jordana T [0000-0002-3858-5986], Elliott, Paul [0000-0002-7511-5684], Brenner, Hermann [0000-0002-6129-1572], Beekman, Marian [0000-0003-0585-6206], Waldenberger, Melanie [0000-0003-0583-5093], Chambers, John C [0000-0003-0209-4541], Dehghan, Abbas [0000-0001-6403-016X], Järvelin, Marjo-Riitta [0000-0002-2149-0630], Apollo - University of Cambridge Repository, Maastricht Centre for Systems Biology, RS: FSE MaCSBio, Tampere University, Clinical Medicine, Department of Clinical Chemistry, BioMediTech, Department of Clinical Physiology and Nuclear Medicine, Ong, Kenneth [0000-0003-4689-7530], Internal Medicine, and Epidemiology

Subjects
obesity, BLOOD, 45/61, PREDICTION, NF-KAPPA-B, BIOS consortium, General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, 38, Low grade inflammation, MARKERS, SDG 3 - Good Health and Well-being, Inflammation/genetics, risk factors, Medicine, Humans, TRANSCRIPTION, Nucleotide Motifs, C-Reactive Protein, CpG Islands, DNA Methylation, Inflammation, EPIGENOME-WIDE ASSOCIATION, DNA methylation, Multidisciplinary, business.industry, article, 631/208/176/1988, 692/163/2743/393, Cardiorespiratory fitness, General Chemistry, CpG Islands/genetics, LIFETIME RISK, GENOME, BODY-MASS INDEX, Immunology, 3111 Biomedicine, C-Reactive Protein/genetics, business, 692/499, DNA Methylation/genetics
Abstract

Chronic inflammation, marked by C-reactive protein, has been associated with changes in methylation, but the causal relationship is unclear. Here, the authors perform a Epigenome-wide association meta-analysis for C-reactive protein levels and find that these methylation changes are likely the consequence of inflammation and could contribute to disease.We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.

Published
2022

2. An integrative analysis of clinical and epigenetic biomarkers of mortality

Author

Tianxiao Huan, Steve Nguyen, Elena Colicino, Carolina Ochoa-Rosales, W. David Hill, Jennifer A. Brody, Mette Soerensen, Yan Zhang, Antoine Baldassari, Mohamed Ahmed Elhadad, Tanaka Toshiko, Yinan Zheng, Arce Domingo-Relloso, Dong Heon Lee, Jiantao Ma, Chen Yao, Chunyu Liu, Shih-Jen Hwang, Roby Joehanes, Myriam Fornage, Jan Bressler, Joyce BJ van Meurs, Birgit Debrabant, Jonas Mengel-From, Jacob Hjelmborg, Kaare Christensen, Pantel Vokonas, Joel Schwartz, Sina A. Gahrib, Nona Sotoodehnia, Colleen M. Sitlani, Sonja Kunze, Christian Gieger, Annette Peters, Melanie Waldenberger, Ian J. Deary, Luigi Ferrucci, Yishu Qu, Philip Greenland, Donald M Lloyd-Jones, Lifang Hou, Stefania Bandinelli, Trudy Voortman, Brenner Hermann, Andrea Baccarelli, Eric Whitsel, James S. Pankow, and Daniel Levy

Abstract

DNA methylation (DNAm) has been reported to be associated with many diseases and mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction.We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n=15,013). During a mean follow-up of 10 years, there were 4314 deaths from all-causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at P-7, of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk independent of clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed a substantial improvement in prediction of cancer death with 11% and 5% increase in the C-index in internal and external replications, compared with the model trained by clinical risk factors alone. Mendelian randomization identified 15 CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta=1.2, PMR=4.1x10-4), and negatively associated with longevity (Beta=-1.9, PMR=0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune and cancer related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.

Published
2022

3. Genome-wide association of phenotypes based on clustering patterns of hand osteoarthritis identify

Author

Cindy Germaine, Boer, Michelle S, Yau, Sarah J, Rice, Rodrigo, Coutinho de Almeida, Kathleen, Cheung, Unnur, Styrkarsdottir, Lorraine, Southam, Linda, Broer, Jeremy Mark, Wilkinson, André G, Uitterlinden, Eleftheria, Zeggini, David, Felson, John, Loughlin, Mariel, Young, Terence Dante, Capellini, Ingrid, Meulenbelt, and Joyce Bj, van Meurs

Subjects
Hand Joints, Fibrillar Collagens, polymorphism, Wnt Proteins, Phenotype, Osteoarthritis, Cluster Analysis, Humans, epidemiology, genetic, Genome-Wide Association Study
Abstract

Background Despite recent advances in the understanding of the genetic architecture of osteoarthritis (OA), only two genetic loci have been identified for OA of the hand, in part explained by the complexity of the different hand joints and heterogeneity of OA pathology. Methods We used data from the Rotterdam Study (RSI, RSII and RSIII) to create three hand OA phenotypes based on clustering patterns of radiographic OA severity to increase power in our modest discovery genome-wide association studies in the RS (n=8700), and sought replication in an independent cohort, the Framingham Heart Study (n=1203). We used multiple approaches that leverage different levels of information and functional data to further investigate the underlying biological mechanisms and candidate genes for replicated loci. We also attempted to replicate known OA loci at other joint sites, including the hips and knees. Results We found two novel genome-wide significant loci for OA in the thumb joints. We identified WNT9A as a possible novel causal gene involved in OA pathogenesis. Furthermore, several previously identified genetic loci for OA seem to confer risk for OA across multiple joints: TGFa, RUNX2, COL27A1, ASTN2, IL11 and GDF5 loci. Conclusions We identified a robust novel genetic locus for hand OA on chromosome 1, of which WNT9A is the most likely causal gene. In addition, multiple genetic loci were identified to be associated with OA across multiple joints. Our study confirms the potential for novel insight into the genetic architecture of OA by using biologically meaningful stratified phenotypes.

Published
2020

4. DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases

Author

Ligthart, Symen, Marzi, Carola, Aslibekyan, Stella, Mendelson, Michael M, Conneely, Karen N, Tanaka, Toshiko, Colicino, Elena, Waite, Lindsay L, Joehanes, Roby, Guan, Weihua, Brody, Jennifer A, Elks, Cathy, Marioni, Riccardo, Jhun, Min A, Agha, Golareh, Bressler, Jan, Ward-Caviness, Cavin K, Chen, Brian H, Huan, Tianxiao, Bakulski, Kelly, Salfati, Elias L, WHI-EMPC Investigators, Fiorito, Giovanni, CHARGE epigenetics of Coronary Heart Disease, Wahl, Simone, Schramm, Katharina, Sha, Jin, Hernandez, Dena G, Just, Allan C, Smith, Jennifer A, Sotoodehnia, Nona, Pilling, Luke C, Pankow, James S, Tsao, Phil S, Liu, Chunyu, Zhao, Wei, Guarrera, Simonetta, Michopoulos, Vasiliki J, Smith, Alicia K, Peters, Marjolein J, Melzer, David, Vokonas, Pantel, Fornage, Myriam, Prokisch, Holger, Bis, Joshua C, Chu, Audrey Y, Herder, Christian, Grallert, Harald, Yao, Chen, Shah, Sonia, McRae, Allan F, Lin, Honghuang, Horvath, Steve, Fallin, Daniele, Hofman, Albert, Wareham, Nicholas J, Wiggins, Kerri L, Feinberg, Andrew P, Starr, John M, Visscher, Peter M, Murabito, Joanne M, Kardia, Sharon LR, Absher, Devin M, Binder, Elisabeth B, Singleton, Andrew B, Bandinelli, Stefania, Peters, Annette, Waldenberger, Melanie, Matullo, Giuseppe, Schwartz, Joel D, Demerath, Ellen W, Uitterlinden, André G, van Meurs, Joyce BJ, Franco, Oscar H, Chen, Yii-Der Ida, Levy, Daniel, Turner, Stephen T, Deary, Ian J, Ressler, Kerry J, Dupuis, Josée, Ferrucci, Luigi, Ong, Ken K, Assimes, Themistocles L, Boerwinkle, Eric, Koenig, Wolfgang, Arnett, Donna K, Baccarelli, Andrea A, Benjamin, Emelia J, Dehghan, Abbas, Wareham, Nicholas [0000-0003-1422-2993], Ong, Kenneth [0000-0003-4689-7530], and Apollo - University of Cambridge Repository

Subjects
Male, Inflammation, DNA methylation, Quantitative Trait Loci, Diabetes, Gene Expression, Genetic Variation, White People, Epigenesis, Genetic, C-reactive protein, Black or African American, Coronary heart disease, Epigenome-wide association study, Humans, CpG Islands, Female, Nucleotide Motifs, Body mass index, Genome-Wide Association Study
Abstract

Background: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.Results: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P –7) in the discovery panel of European ancestry and replicated (P –4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P –5), ten (17%) CpG sites were associated with a nearby genetic variant (P –3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P –5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.Conclusion: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.

Published
2016

5. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture

Author

Zheng, Hou-Feng, Forgetta, Vincenzo, Hsu, Yi-Hsiang, Estrada, Karol, Rosello-Diez, Alberto, Leo, Paul J, Dahia, Chitra L, Park-Min, Kyung Hyun, Tobias, Jonathan H, Kooperberg, Charles, Kleinman, Aaron, Styrkarsdottir, Unnur, Liu, Ching-Ti, Uggla, Charlotta, Evans, Daniel S, Nielson, Carrie M, Walter, Klaudia, Pettersson-Kymmer, Ulrika, McCarthy, Shane, Eriksson, Joel, Kwan, Tony, Jhamai, Mila, Trajanoska, Katerina, Memari, Yasin, Min, Josine, Huang, Jie, Danecek, Petr, Wilmot, Beth, Li, Rui, Chou, Wen-Chi, Mokry, Lauren E, Moayyeri, Alireza, Claussnitzer, Melina, Cheng, Chia-Ho, Cheung, Warren, Medina-Gómez, Carolina, Ge, Bing, Chen, Shu-Huang, Choi, Kwangbom, Oei, Ling, Fraser, James, Kraaij, Robert, Hibbs, Matthew A, Gregson, Celia L, Paquette, Denis, Hofman, Albert, Wibom, Carl, Tranah, Gregory J, Marshall, Mhairi, Gardiner, Brooke B, Cremin, Katie, Auer, Paul, Hsu, Li, Ring, Sue, Tung, Joyce Y, Thorleifsson, Gudmar, Enneman, Anke W, van Schoor, Natasja M, de Groot, Lisette CPGM, van der Velde, Nathalie, Melin, Beatrice, Kemp, John P, Christiansen, Claus, Sayers, Adrian, Zhou, Yanhua, Calderari, Sophie, van Rooij, Jeroen, Carlson, Chris, Peters, Ulrike, Berlivet, Soizik, Dostie, Josée, Uitterlinden, Andre G, Williams, Stephen R, Farber, Charles, Grinberg, Daniel, LaCroix, Andrea Z, Haessler, Jeff, Chasman, Daniel I, Giulianini, Franco, Rose, Lynda M, Ridker, Paul M, Eisman, John A, Nguyen, Tuan V, Center, Jacqueline R, Nogues, Xavier, Garcia-Giralt, Natalia, Launer, Lenore L, Gudnason, Vilmunder, Mellström, Dan, Vandenput, Liesbeth, Amin, Najaf, van Duijn, Cornelia M, Karlsson, Magnus K, Ljunggren, Östen, Svensson, Olle, Hallmans, Göran, Rousseau, François, Giroux, Sylvie, Bussière, Johanne, Arp, Pascal P, Koromani, Fjorda, Prince, Richard L, Lewis, Joshua R, Langdahl, Bente L, Hermann, A Pernille, Jensen, Jens-Erik B, Kaptoge, Stephen, Khaw, Kay-Tee, Reeve, Jonathan, Formosa, Melissa M, Xuereb-Anastasi, Angela, Åkesson, Kristina, McGuigan, Fiona E, Garg, Gaurav, Olmos, Jose M, Zarrabeitia, Maria T, Riancho, Jose A, Ralston, Stuart H, Alonso, Nerea, Jiang, Xi, Goltzman, David, Pastinen, Tomi, Grundberg, Elin, Gauguier, Dominique, Orwoll, Eric S, Karasik, David, Davey-Smith, George, AOGC Consortium, Smith, Albert V, Siggeirsdottir, Kristin, Harris, Tamara B, Zillikens, M Carola, van Meurs, Joyce BJ, Thorsteinsdottir, Unnur, Maurano, Matthew T, Timpson, Nicholas J, Soranzo, Nicole, Durbin, Richard, Wilson, Scott G, Ntzani, Evangelia E, Brown, Matthew A, Stefansson, Kari, Hinds, David A, Spector, Tim, Cupples, L Adrienne, Ohlsson, Claes, Greenwood, Celia MT, UK10K Consortium, Jackson, Rebecca D, Rowe, David W, Loomis, Cynthia A, Evans, David M, Ackert-Bicknell, Cheryl L, Joyner, Alexandra L, Duncan, Emma L, Kiel, Douglas P, Rivadeneira, Fernando, and Richards, J Brent

Subjects
Homeodomain Proteins, Genotype, Genome, Human, General Science & Technology, European Continental Ancestry Group, Genetic Variation, Sequence Analysis, DNA, Genomics, Bone and Bones, Europe, Wnt Proteins, Mice, Disease Models, Animal, Fractures, Bone, AOGC Consortium, Gene Frequency, Bone Density, MD Multidisciplinary, UK10K Consortium, Animals, Humans, Genetic Predisposition to Disease, Female, Exome
Abstract

The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

Published
2015

6. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture

Author

Zheng, Hou-Feng, Forgetta, Vincenzo, Hsu, Yi-Hsiang, Estrada, Karol, Rosello-Diez, Alberto, Leo, Paul J, Dahia, Chitra L, Park-Min, Kyung Hyun, Tobias, Jonathan H, Kooperberg, Charles, Kleinman, Aaron, Styrkarsdottir, Unnur, Liu, Ching-Ti, Uggla, Charlotta, Evans, Daniel S, Nielson, Carrie M, Walter, Klaudia, Pettersson-Kymmer, Ulrika, McCarthy, Shane, Eriksson, Joel, Kwan, Tony, Jhamai, Mila, Trajanoska, Katerina, Memari, Yasin, Min, Josine, Huang, Jie, Danecek, Petr, Wilmot, Beth, Li, Rui, Chou, Wen-Chi, Mokry, Lauren E, Moayyeri, Alireza, Claussnitzer, Melina, Cheng, Chia-Ho, Cheung, Warren, Medina-Gómez, Carolina, Ge, Bing, Chen, Shu-Huang, Choi, Kwangbom, Oei, Ling, Fraser, James, Kraaij, Robert, Hibbs, Matthew A, Gregson, Celia L, Paquette, Denis, Hofman, Albert, Wibom, Carl, Tranah, Gregory J, Marshall, Mhairi, Gardiner, Brooke B, Cremin, Katie, Auer, Paul, Hsu, Li, Ring, Sue, Tung, Joyce Y, Thorleifsson, Gudmar, Enneman, Anke W, Van Schoor, Natasja M, De Groot, Lisette CPGM, Van Der Velde, Nathalie, Melin, Beatrice, Kemp, John P, Christiansen, Claus, Sayers, Adrian, Zhou, Yanhua, Calderari, Sophie, Van Rooij, Jeroen, Carlson, Chris, Peters, Ulrike, Berlivet, Soizik, Dostie, Josée, Uitterlinden, Andre G, Williams, Stephen R, Farber, Charles, Grinberg, Daniel, LaCroix, Andrea Z, Haessler, Jeff, Chasman, Daniel I, Giulianini, Franco, Rose, Lynda M, Ridker, Paul M, Eisman, John A, Nguyen, Tuan V, Center, Jacqueline R, Nogues, Xavier, Garcia-Giralt, Natalia, Launer, Lenore L, Gudnason, Vilmunder, Mellström, Dan, Vandenput, Liesbeth, Amin, Najaf, Van Duijn, Cornelia M, Karlsson, Magnus K, Ljunggren, Östen, Svensson, Olle, Hallmans, Göran, Rousseau, François, Giroux, Sylvie, Bussière, Johanne, Arp, Pascal P, Koromani, Fjorda, Prince, Richard L, Lewis, Joshua R, Langdahl, Bente L, Hermann, A Pernille, Jensen, Jens-Erik B, Kaptoge, Stephen, Khaw, Kay-Tee, Reeve, Jonathan, Formosa, Melissa M, Xuereb-Anastasi, Angela, Åkesson, Kristina, McGuigan, Fiona E, Garg, Gaurav, Olmos, Jose M, Zarrabeitia, Maria T, Riancho, Jose A, Ralston, Stuart H, Alonso, Nerea, Jiang, Xi, Goltzman, David, Pastinen, Tomi, Grundberg, Elin, Gauguier, Dominique, Orwoll, Eric S, Karasik, David, Davey-Smith, George, AOGC Consortium, Smith, Albert V, Siggeirsdottir, Kristin, Harris, Tamara B, Zillikens, M Carola, Van Meurs, Joyce BJ, Thorsteinsdottir, Unnur, Maurano, Matthew T, Timpson, Nicholas J, Soranzo, Nicole, Durbin, Richard, Wilson, Scott G, Ntzani, Evangelia E, Brown, Matthew A, Stefansson, Kari, Hinds, David A, Spector, Tim, Cupples, L Adrienne, Ohlsson, Claes, Greenwood, Celia MT, UK10K Consortium, Jackson, Rebecca D, Rowe, David W, Loomis, Cynthia A, Evans, David M, Ackert-Bicknell, Cheryl L, Joyner, Alexandra L, Duncan, Emma L, Kiel, Douglas P, Rivadeneira, Fernando, Richards, J Brent, Rosello-Diez, Alberto [0000-0002-5550-9846], Kaptoge, Stephen [0000-0002-1155-4872], Khaw, Kay-Tee [0000-0002-8802-2903], Soranzo, Nicole [0000-0003-1095-3852], and Apollo - University of Cambridge Repository

Subjects
Homeodomain Proteins, Genotype, Genome, Human, Genetic Variation, Genomics, Sequence Analysis, DNA, Bone and Bones, White People, Europe, Wnt Proteins, Disease Models, Animal, Fractures, Bone, Mice, Gene Frequency, Bone Density, Animals, Humans, Exome, Female, Genetic Predisposition to Disease
Abstract

The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

Published
2015

7. 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, International Consortium For Blood Pressure GWAS (ICBP), Vasan, Ramachandran, O'Donnell, Christopher J, Munson, Peter J, Yang, Xia, Prokisch, Holger, Völker, Uwe, Van Meurs, Joyce BJ, Ferrucci, Luigi, and Levy, Daniel

Subjects
Gene Expression Regulation, Genotype, Hypertension, Humans, Blood Pressure, Genetic Predisposition to Disease, Transcriptome, Polymorphism, Single Nucleotide, 3. Good health, Genome-Wide Association Study
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

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