Browsing by Subject "PARTITIONING HERITABILITY"

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  • Guo, Michael H.; Nandakumar, Satish K.; Ulirsch, Jacob C.; Zekavat, Seyedeh M.; Buenrostro, Jason D.; Natarajan, Pradeep; Salem, Rany M.; Chiarle, Roberto; Mitt, Mario; Kals, Mart; Pärn, Kalle; Fischer, Krista; Milani, Lili; Magi, Reedik; Palta, Priit; Gabriel, Stacey B.; Metspalu, Andres; Lander, Eric S.; Kathiresan, Sekar; Hirschhorn, Joel N.; Esko, Tonu; Sankaran, Vijay G. (2017)
    Genetic variants affecting hematopoiesis can influence commonly measured blood cell traits. To identify factors that affect hematopoiesis, we performed association studies for blood cell traits in the population-based Estonian Biobank using high-coverage whole-genome sequencing (WGS) in 2,284 samples and SNP genotyping in an additional 14,904 samples. Using up to 7,134 samples with available phenotype data, our analyses identified 17 associations across 14 blood cell traits. Integration of WGS-based fine-mapping and complementary epigenomic datasets provided evidence for causal mechanisms at several loci, including at a previously undiscovered basophil count-associated locus near the master hematopoietic transcription factor CEBPA. The fine-mapped variant at this basophil count association near CEBPA overlapped an enhancer active in common myeloid progenitors and influenced its activity. In situ perturbation of this enhancer by CRISPR/Cas9 mutagenesis in hematopoietic stem and progenitor cells demonstrated that it is necessary for and specifically regulates CEBPA expression during basophil differentiation. We additionally identified basophil count-associated variation at another more pleiotropic myeloid enhancer near GATA2, highlighting regulatory mechanisms for ordered expression of master hematopoietic regulators during lineage specification. Our study illustrates how population-based genetic studies can provide key insights into poorly understood cell differentiation processes of considerable physiologic relevance.
  • Psychiat Genomics Consortium; Lönnqvist, Jouko; Paunio, Tiina (2018)
    Genetic correlation is a key population parameter that describes the shared genetic architecture of complex traits and diseases. It can be estimated by current state-of-art methods, i.e., linkage disequilibrium score regression (LDSC) and genomic restricted maximum likelihood (GREML). The massively reduced computing burden of LDSC compared to GREML makes it an attractive tool, although the accuracy (i.e., magnitude of standard errors) of LDSC estimates has not been thoroughly studied. In simulation, we show that the accuracy of GREML is generally higher than that of LDSC. When there is genetic heterogeneity between the actual sample and reference data from which LD scores are estimated, the accuracy of LDSC decreases further. In real data analyses estimating the genetic correlation between schizophrenia (SCZ) and body mass index, we show that GREML estimates based on similar to 150,000 individuals give a higher accuracy than LDSC estimates based on similar to 400,000 individuals (from combinedmeta-data). A GREML genomic partitioning analysis reveals that the genetic correlation between SCZ and height is significantly negative for regulatory regions, which whole genome or LDSC approach has less power to detect. We conclude that LDSC estimates should be carefully interpreted as there can be uncertainty about homogeneity among combined meta-datasets. We suggest that any interesting findings from massive LDSC analysis for a large number of complex traits should be followed up, where possible, with more detailed analyses with GREML methods, even if sample sizes are lesser.
  • 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.