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8. Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data

Author

Wainschtein, Pierrick, Jain, Deepti, Zheng, Zhili, Cupples, L Adrienne, Shadyab, Aladdin H, McKnight, Barbara, Shoemaker, Benjamin M, Mitchell, Braxton D, Psaty, Bruce M, Kooperberg, Charles, Liu, Ching-Ti, Albert, Christine M, Roden, Dan, Chasman, Daniel I, Darbar, Dawood, Lloyd-Jones, Donald M, Arnett, Donna K, Regan, Elizabeth A, Boerwinkle, Eric, Rotter, Jerome I, O’Connell, Jeffrey R, Yanek, Lisa R, de Andrade, Mariza, Allison, Matthew A, McDonald, Merry-Lynn N, Chung, Mina K, Fornage, Myriam, Chami, Nathalie, Smith, Nicholas L, Ellinor, Patrick T, Vasan, Ramachandran S, Mathias, Rasika A, Loos, Ruth JF, Rich, Stephen S, Lubitz, Steven A, Heckbert, Susan R, Redline, Susan, Guo, Xiuqing, Chen, Y-D Ida, Laurie, Cecelia A, Hernandez, Ryan D, McGarvey, Stephen T, Goddard, Michael E, Laurie, Cathy C, North, Kari E, Lange, Leslie A, Weir, Bruce S, Yengo, Loic, Yang, Jian, and Visscher, Peter M

Subjects
Human Genome, Genetics, 2.1 Biological and endogenous factors, Aetiology, Generic health relevance, Alleles, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Multifactorial Inheritance, Polymorphism, Single Nucleotide, TOPMed Anthropometry Working Group, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Analyses of data from genome-wide association studies on unrelated individuals have shown that, for human traits and diseases, approximately one-third to two-thirds of heritability is captured by common SNPs. However, it is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular whether the causal variants are rare, or whether it is overestimated due to bias in inference from pedigree data. Here we estimated heritability for height and body mass index (BMI) from whole-genome sequence data on 25,465 unrelated individuals of European ancestry. The estimated heritability was 0.68 (standard error 0.10) for height and 0.30 (standard error 0.10) for body mass index. Low minor allele frequency variants in low linkage disequilibrium (LD) with neighboring variants were enriched for heritability, to a greater extent for protein-altering variants, consistent with negative selection. Our results imply that rare variants, in particular those in regions of low linkage disequilibrium, are a major source of the still missing heritability of complex traits and disease.

Published
2022

9. Assortative mating biases marker-based heritability estimators

Author

Border, Richard, O’Rourke, Sean, de Candia, Teresa, Goddard, Michael E, Visscher, Peter M, Yengo, Loic, Jones, Matt, and Keller, Matthew C

Subjects
Biological Sciences, Genetics, Biological Psychology, Statistics, Mathematical Sciences, Psychology, Algorithms, Bias, Computer Simulation, Female, Genetics, Population, Genome-Wide Association Study, Humans, Likelihood Functions, Linkage Disequilibrium, Male, Mendelian Randomization Analysis, Models, Genetic, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable, Reproduction
Abstract

Many traits are subject to assortative mating, with recent molecular genetic findings confirming longstanding theoretical predictions that assortative mating induces long range dependence across causal variants. However, all marker-based heritability estimators implicitly assume mating is random. We provide mathematical and simulation-based evidence demonstrating that both method-of-moments and likelihood-based estimators are biased in the presence of assortative mating and derive corrected heritability estimators for traits subject to assortment. Finally, we demonstrate that the empirical patterns of estimates across methods and sample sizes for real traits subject to assortative mating are congruent with expected assortative mating-induced biases. For example, marker-based heritability estimates for height are 14% - 23% higher than corrected estimates using UK Biobank data.

Published
2022

11. A saturated map of common genetic variants associated with human height

Author

Yengo, Loïc, Vedantam, Sailaja, Marouli, Eirini, Sidorenko, Julia, Bartell, Eric, Sakaue, Saori, Graff, Marielisa, Eliasen, Anders U., Jiang, Yunxuan, Raghavan, Sridharan, Miao, Jenkai, Arias, Joshua D., Graham, Sarah E., Mukamel, Ronen E., Spracklen, Cassandra N., Yin, Xianyong, Chen, Shyh-Huei, Ferreira, Teresa, Highland, Heather H., Ji, Yingjie, Karaderi, Tugce, Lin, Kuang, Lüll, Kreete, Malden, Deborah E., Medina-Gomez, Carolina, Machado, Moara, Moore, Amy, Rüeger, Sina, Sim, Xueling, Vrieze, Scott, Ahluwalia, Tarunveer S., Akiyama, Masato, Allison, Matthew A., Alvarez, Marcus, Andersen, Mette K., Ani, Alireza, Appadurai, Vivek, Arbeeva, Liubov, Bhaskar, Seema, Bielak, Lawrence F., Bollepalli, Sailalitha, Bonnycastle, Lori L., Bork-Jensen, Jette, Bradfield, Jonathan P., Bradford, Yuki, Braund, Peter S., Brody, Jennifer A., Burgdorf, Kristoffer S., Cade, Brian E., Cai, Hui, Cai, Qiuyin, Campbell, Archie, Cañadas-Garre, Marisa, Catamo, Eulalia, Chai, Jin-Fang, Chai, Xiaoran, Chang, Li-Ching, Chang, Yi-Cheng, Chen, Chien-Hsiun, Chesi, Alessandra, Choi, Seung Hoan, Chung, Ren-Hua, Cocca, Massimiliano, Concas, Maria Pina, Couture, Christian, Cuellar-Partida, Gabriel, Danning, Rebecca, Daw, E. Warwick, Degenhard, Frauke, Delgado, Graciela E., Delitala, Alessandro, Demirkan, Ayse, Deng, Xuan, Devineni, Poornima, Dietl, Alexander, Dimitriou, Maria, Dimitrov, Latchezar, Dorajoo, Rajkumar, Ekici, Arif B., Engmann, Jorgen E., Fairhurst-Hunter, Zammy, Farmaki, Aliki-Eleni, Faul, Jessica D., Fernandez-Lopez, Juan-Carlos, Forer, Lukas, Francescatto, Margherita, Freitag-Wolf, Sandra, Fuchsberger, Christian, Galesloot, Tessel E., Gao, Yan, Gao, Zishan, Geller, Frank, Giannakopoulou, Olga, Giulianini, Franco, Gjesing, Anette P., Goel, Anuj, Gordon, Scott D., Gorski, Mathias, Grove, Jakob, Guo, Xiuqing, Gustafsson, Stefan, Haessler, Jeffrey, Hansen, Thomas F., Havulinna, Aki S., Haworth, Simon J., He, Jing, Heard-Costa, Nancy, Hebbar, Prashantha, Hindy, George, Ho, Yuk-Lam A., Hofer, Edith, Holliday, Elizabeth, Horn, Katrin, Hornsby, Whitney E., Hottenga, Jouke-Jan, Huang, Hongyan, Huang, Jie, Huerta-Chagoya, Alicia, Huffman, Jennifer E., Hung, Yi-Jen, Huo, Shaofeng, Hwang, Mi Yeong, Iha, Hiroyuki, Ikeda, Daisuke D., Isono, Masato, Jackson, Anne U., Jäger, Susanne, Jansen, Iris E., Johansson, Ingegerd, Jonas, Jost B., Jonsson, Anna, Jørgensen, Torben, Kalafati, Ioanna-Panagiota, Kanai, Masahiro, Kanoni, Stavroula, Kårhus, Line L., Kasturiratne, Anuradhani, Katsuya, Tomohiro, Kawaguchi, Takahisa, Kember, Rachel L., Kentistou, Katherine A., Kim, Han-Na, Kim, Young Jin, Kleber, Marcus E., Knol, Maria J., Kurbasic, Azra, Lauzon, Marie, Le, Phuong, Lea, Rodney, Lee, Jong-Young, Leonard, Hampton L., Li, Shengchao A., Li, Xiaohui, Li, Xiaoyin, Liang, Jingjing, Lin, Honghuang, Lin, Shih-Yi, Liu, Jun, Liu, Xueping, Lo, Ken Sin, Long, Jirong, Lores-Motta, Laura, Luan, Jian’an, Lyssenko, Valeriya, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Mamakou, Vasiliki, Mangino, Massimo, Manichaikul, Ani, Marten, Jonathan, Mattheisen, Manuel, Mavarani, Laven, McDaid, Aaron F., Meidtner, Karina, Melendez, Tori L., Mercader, Josep M., Milaneschi, Yuri, Miller, Jason E., Millwood, Iona Y., Mishra, Pashupati P., Mitchell, Ruth E., Møllehave, Line T., Morgan, Anna, Mucha, Soeren, Munz, Matthias, Nakatochi, Masahiro, Nelson, Christopher P., Nethander, Maria, Nho, Chu Won, Nielsen, Aneta A., Nolte, Ilja M., Nongmaithem, Suraj S., Noordam, Raymond, Ntalla, Ioanna, Nutile, Teresa, Pandit, Anita, Christofidou, Paraskevi, Pärna, Katri, Pauper, Marc, Petersen, Eva R. B., Petersen, Liselotte V., Pitkänen, Niina, Polašek, Ozren, Poveda, Alaitz, Preuss, Michael H., Pyarajan, Saiju, Raffield, Laura M., Rakugi, Hiromi, Ramirez, Julia, Rasheed, Asif, Raven, Dennis, Rayner, Nigel W., Riveros, Carlos, Rohde, Rebecca, Ruggiero, Daniela, Ruotsalainen, Sanni E., Ryan, Kathleen A., Sabater-Lleal, Maria, Saxena, Richa, Scholz, Markus, Sendamarai, Anoop, Shen, Botong, Shi, Jingchunzi, Shin, Jae Hun, Sidore, Carlo, Sitlani, Colleen M., Slieker, Roderick C., Smit, Roelof A. J., Smith, Albert V., Smith, Jennifer A., Smyth, Laura J., Southam, Lorraine, Steinthorsdottir, Valgerdur, Sun, Liang, Takeuchi, Fumihiko, Tallapragada, Divya Sri Priyanka, Taylor, Kent D., Tayo, Bamidele O., Tcheandjieu, Catherine, Terzikhan, Natalie, Tesolin, Paola, Teumer, Alexander, Theusch, Elizabeth, Thompson, Deborah J., Thorleifsson, Gudmar, Timmers, Paul R. H. J., Trompet, Stella, Turman, Constance, Vaccargiu, Simona, van der Laan, Sander W., van der Most, Peter J., van Klinken, Jan B., van Setten, Jessica, Verma, Shefali S., Verweij, Niek, Veturi, Yogasudha, Wang, Carol A., Wang, Chaolong, Wang, Lihua, Wang, Zhe, Warren, Helen R., Bin Wei, Wen, Wickremasinghe, Ananda R., Wielscher, Matthias, Wiggins, Kerri L., Winsvold, Bendik S., Wong, Andrew, Wu, Yang, Wuttke, Matthias, Xia, Rui, Xie, Tian, Yamamoto, Ken, Yang, Jingyun, Yao, Jie, Young, Hannah, Yousri, Noha A., Yu, Lei, Zeng, Lingyao, Zhang, Weihua, Zhang, Xinyuan, Zhao, Jing-Hua, Zhao, Wei, Zhou, Wei, Zimmermann, Martina E., Zoledziewska, Magdalena, Adair, Linda S., Adams, Hieab H. H., Aguilar-Salinas, Carlos A., Al-Mulla, Fahd, Arnett, Donna K., Asselbergs, Folkert W., Åsvold, Bjørn Olav, Attia, John, Banas, Bernhard, Bandinelli, Stefania, Bennett, David A., Bergler, Tobias, Bharadwaj, Dwaipayan, Biino, Ginevra, Bisgaard, Hans, Boerwinkle, Eric, Böger, Carsten A., Bønnelykke, Klaus, Boomsma, Dorret I., Børglum, Anders D., Borja, Judith B., Bouchard, Claude, Bowden, Donald W., Brandslund, Ivan, Brumpton, Ben, Buring, Julie E., Caulfield, Mark J., Chambers, John C., Chandak, Giriraj R., Chanock, Stephen J., Chaturvedi, Nish, Chen, Yii-Der Ida, Chen, Zhengming, Cheng, Ching-Yu, Christophersen, Ingrid E., Ciullo, Marina, Cole, John W., Collins, Francis S., Cooper, Richard S., Cruz, Miguel, Cucca, Francesco, Cupples, L. Adrienne, Cutler, Michael J., Damrauer, Scott M., Dantoft, Thomas M., de Borst, Gert J., de Groot, Lisette C. P. G. M., De Jager, Philip L., de Kleijn, Dominique P. V., Janaka de Silva, H., Dedoussis, George V., den Hollander, Anneke I., Du, Shufa, Easton, Douglas F., Elders, Petra J. M., Eliassen, A. Heather, Ellinor, Patrick T., Elmståhl, Sölve, Erdmann, Jeanette, Evans, Michele K., Fatkin, Diane, Feenstra, Bjarke, Feitosa, Mary F., Ferrucci, Luigi, Ford, Ian, Fornage, Myriam, Franke, Andre, Franks, Paul W., Freedman, Barry I., Gasparini, Paolo, Gieger, Christian, Girotto, Giorgia, Goddard, Michael E., Golightly, Yvonne M., Gonzalez-Villalpando, Clicerio, Gordon-Larsen, Penny, Grallert, Harald, Grant, Struan F. A., Grarup, Niels, Griffiths, Lyn, Gudnason, Vilmundur, Haiman, Christopher, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayward, Caroline, Heckbert, Susan R., Heng, Chew-Kiat, Hengstenberg, Christian, Hewitt, Alex W., Hishigaki, Haretsugu, Hoyng, Carel B., Huang, Paul L., Huang, Wei, Hunt, Steven C., Hveem, Kristian, Hyppönen, Elina, Iacono, William G., Ichihara, Sahoko, Ikram, M. Arfan, Isasi, Carmen R., Jackson, Rebecca D., Jarvelin, Marjo-Riitta, Jin, Zi-Bing, Jöckel, Karl-Heinz, Joshi, Peter K., Jousilahti, Pekka, Jukema, J. Wouter, Kähönen, Mika, Kamatani, Yoichiro, Kang, Kui Dong, Kaprio, Jaakko, Kardia, Sharon L. R., Karpe, Fredrik, Kato, Norihiro, Kee, Frank, Kessler, Thorsten, Khera, Amit V., Khor, Chiea Chuen, Kiemeney, Lambertus A. L. M., Kim, Bong-Jo, Kim, Eung Kweon, Kim, Hyung-Lae, Kirchhof, Paulus, Kivimaki, Mika, Koh, Woon-Puay, Koistinen, Heikki A., Kolovou, Genovefa D., Kooner, Jaspal S., Kooperberg, Charles, Köttgen, Anna, Kovacs, Peter, Kraaijeveld, Adriaan, Kraft, Peter, Krauss, Ronald M., Kumari, Meena, Kutalik, Zoltan, Laakso, Markku, Lange, Leslie A., Langenberg, Claudia, Launer, Lenore J., Le Marchand, Loic, Lee, Hyejin, Lee, Nanette R., Lehtimäki, Terho, Li, Huaixing, Li, Liming, Lieb, Wolfgang, Lin, Xu, Lind, Lars, Linneberg, Allan, Liu, Ching-Ti, Liu, Jianjun, Loeffler, Markus, London, Barry, Lubitz, Steven A., Lye, Stephen J., Mackey, David A., Mägi, Reedik, Magnusson, Patrik K. E., Marcus, Gregory M., Vidal, Pedro Marques, Martin, Nicholas G., März, Winfried, Matsuda, Fumihiko, McGarrah, Robert W., McGue, Matt, McKnight, Amy Jayne, Medland, Sarah E., Mellström, Dan, Metspalu, Andres, Mitchell, Braxton D., Mitchell, Paul, Mook-Kanamori, Dennis O., Morris, Andrew D., Mucci, Lorelei A., Munroe, Patricia B., Nalls, Mike A., Nazarian, Saman, Nelson, Amanda E., Neville, Matt J., Newton-Cheh, Christopher, Nielsen, Christopher S., Nöthen, Markus M., Ohlsson, Claes, Oldehinkel, Albertine J., Orozco, Lorena, Pahkala, Katja, Pajukanta, Päivi, Palmer, Colin N. A., Parra, Esteban J., Pattaro, Cristian, Pedersen, Oluf, Pennell, Craig E., Penninx, Brenda W. J. H., Perusse, Louis, Peters, Annette, Peyser, Patricia A., Porteous, David J., Posthuma, Danielle, Power, Chris, Pramstaller, Peter P., Province, Michael A., Qi, Qibin, Qu, Jia, Rader, Daniel J., Raitakari, Olli T., Ralhan, Sarju, Rallidis, Loukianos S., Rao, Dabeeru C., Redline, Susan, Reilly, Dermot F., Reiner, Alexander P., Rhee, Sang Youl, Ridker, Paul M., Rienstra, Michiel, Ripatti, Samuli, Ritchie, Marylyn D., Roden, Dan M., Rosendaal, Frits R., Rotter, Jerome I., Rudan, Igor, Rutters, Femke, Sabanayagam, Charumathi, Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sanghera, Dharambir K., Sattar, Naveed, Schmidt, Börge, Schmidt, Helena, Schmidt, Reinhold, Schulze, Matthias B., Schunkert, Heribert, Scott, Laura J., Scott, Rodney J., Sever, Peter, Shiroma, Eric J., Shoemaker, M. Benjamin, Shu, Xiao-Ou, Simonsick, Eleanor M., Sims, Mario, Singh, Jai Rup, Singleton, Andrew B., Sinner, Moritz F., Smith, J. Gustav, Snieder, Harold, Spector, Tim D., Stampfer, Meir J., Stark, Klaus J., Strachan, David P., ‘t Hart, Leen M., Tabara, Yasuharu, Tang, Hua, Tardif, Jean-Claude, Thanaraj, Thangavel A., Timpson, Nicholas J., Tönjes, Anke, Tremblay, Angelo, Tuomi, Tiinamaija, Tuomilehto, Jaakko, Tusié-Luna, Maria-Teresa, Uitterlinden, Andre G., van Dam, Rob M., van der Harst, Pim, Van der Velde, Nathalie, van Duijn, Cornelia M., van Schoor, Natasja M., Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Völzke, Henry, Wacher-Rodarte, Niels H., Walker, Mark, Wang, Ya Xing, Wareham, Nicholas J., Watanabe, Richard M., Watkins, Hugh, Weir, David R., Werge, Thomas M., Widen, Elisabeth, Wilkens, Lynne R., Willemsen, Gonneke, Willett, Walter C., Wilson, James F., Wong, Tien-Yin, Woo, Jeong-Taek, Wright, Alan F., Wu, Jer-Yuarn, Xu, Huichun, Yajnik, Chittaranjan S., Yokota, Mitsuhiro, Yuan, Jian-Min, Zeggini, Eleftheria, Zemel, Babette S., Zheng, Wei, Zhu, Xiaofeng, Zmuda, Joseph M., Zonderman, Alan B., Zwart, John-Anker, Chasman, Daniel I., Cho, Yoon Shin, Heid, Iris M., McCarthy, Mark I., Ng, Maggie C. Y., O’Donnell, Christopher J., Rivadeneira, Fernando, Thorsteinsdottir, Unnur, Sun, Yan V., Tai, E. Shyong, Boehnke, Michael, Deloukas, Panos, Justice, Anne E., Lindgren, Cecilia M., Loos, Ruth J. F., Mohlke, Karen L., North, Kari E., Stefansson, Kari, Walters, Robin G., Winkler, Thomas W., Young, Kristin L., Loh, Po-Ru, Yang, Jian, Esko, Tõnu, Assimes, Themistocles L., Auton, Adam, Abecasis, Goncalo R., Willer, Cristen J., Locke, Adam E., Berndt, Sonja I., Lettre, Guillaume, Frayling, Timothy M., Okada, Yukinori, Wood, Andrew R., Visscher, Peter M., and Hirschhorn, Joel N.

Published
2022
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18. Phantom epistasis between unlinked loci

Author

Hemani, Gibran, Powell, Joseph E., Wang, Huanwei, Shakhbazov, Konstantin, Westra, Harm-Jan, Esko, Tonu, Henders, Anjali K., McRae, Allan F., Martin, Nicholas G., Metspalu, Andres, Franke, Lude, Montgomery, Grant W., Goddard, Michael E., Gibson, Greg, Yang, Jian, and Visscher, Peter M.

Published
2021
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26. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

Author

O'Dushlaine, Colm, Rossin, Lizzy, Lee, Phil H, Duncan, Laramie, Parikshak, Neelroop N, Newhouse, Stephen, Ripke, Stephan, Neale, Benjamin M, Purcell, Shaun M, Posthuma, Danielle, Nurnberger, John I, Lee, S Hong, Faraone, Stephen V, Perlis, Roy H, Mowry, Bryan J, Thapar, Anita, Goddard, Michael E, Witte, John S, Absher, Devin, Agartz, Ingrid, Akil, Huda, Amin, Farooq, Andreassen, Ole A, Anjorin, Adebayo, Anney, Richard, Anttila, Verneri, Arking, Dan E, Asherson, Philip, Azevedo, Maria H, Backlund, Lena, Badner, Judith A, Bailey, Anthony J, Banaschewski, Tobias, Barchas, Jack D, Barnes, Michael R, Barrett, Thomas B, Bass, Nicholas, Battaglia, Agatino, Bauer, Michael, Bayes, Monica, Bellivier, Frank, Bergen, Sarah E, Berrettini, Wade, Betancur, Catalina, Bettecken, Thomas, Biederman, Joseph, Binder, Elisabeth B, Black, Donald W, Blackwood, Douglas HR, Bloss, Cinnamon S, Boehnke, Michael, Boomsma, Dorret I, Breuer, Rene, Bruggeman, Richard, Cormican, Paul, Buccola, Nancy G, Buitelaar, Jan K, Bunney, William E, Buxbaum, Joseph D, Byerley, William F, Byrne, Enda M, Caesar, Sian, Cahn, Wiepke, Cantor, Rita M, Casas, Miguel, Chakravarti, Aravinda, Chambert, Kimberly, Choudhury, Khalid, Cichon, Sven, Mattheisen, Manuel, Cloninger, C Robert, Collier, David A, Cook, Edwin H, Coon, Hilary, Cormand, Bru, Corvin, Aiden, Coryell, William H, Craig, David W, Craig, Ian W, Crosbie, Jennifer, Cuccaro, Michael L, Curtis, David, Czamara, Darina, Datta, Susmita, Dawson, Geraldine, Day, Richard, De Geus, Eco J, Degenhardt, Franziska, Djurovic, Srdjan, Donohoe, Gary J, Doyle, Alysa E, Duan, Jubao, Dudbridge, Frank, Duketis, Eftichia, Ebstein, Richard P, Edenberg, Howard J, Elia, Josephine, Ennis, Sean, Etain, Bruno, and Fanous, Ayman

Subjects
Human Genome, Brain Disorders, Serious Mental Illness, Schizophrenia, Genetics, Depression, Mental Health, Aetiology, 2.1 Biological and endogenous factors, Mental health, Good Health and Well Being, Brain, Databases, Genetic, Genetic Predisposition to Disease, Genome-Wide Association Study, Histones, Humans, Mental Disorders, Signal Transduction, Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium, Neurosciences, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.

Published
2015

27. Estimating Effects and Making Predictions from Genome-Wide Marker Data

Author

Goddard, Michael E., Wray, Naomi R., Verbyla, Klara, and Visscher, Peter M.

Subjects
Statistics - Methodology, Quantitative Biology - Genomics
Abstract

In genome-wide association studies (GWAS), hundreds of thousands of genetic markers (SNPs) are tested for association with a trait or phenotype. Reported effects tend to be larger in magnitude than the true effects of these markers, the so-called ``winner's curse.'' We argue that the classical definition of unbiasedness is not useful in this context and propose to use a different definition of unbiasedness that is a property of the estimator we advocate. We suggest an integrated approach to the estimation of the SNP effects and to the prediction of trait values, treating SNP effects as random instead of fixed effects. Statistical methods traditionally used in the prediction of trait values in the genetics of livestock, which predates the availability of SNP data, can be applied to analysis of GWAS, giving better estimates of the SNP effects and predictions of phenotypic and genetic values in individuals., Comment: Published in at http://dx.doi.org/10.1214/09-STS306 the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org)

Published
2010
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29. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Author

Speliotes, Elizabeth K, Willer, Cristen J, Berndt, Sonja I, Monda, Keri L, Thorleifsson, Gudmar, Jackson, Anne U, Allen, Hana Lango, Lindgren, Cecilia M, Luan, Jian'an, Mägi, Reedik, Randall, Joshua C, Vedantam, Sailaja, Winkler, Thomas W, Qi, Lu, Workalemahu, Tsegaselassie, Heid, Iris M, Steinthorsdottir, Valgerdur, Stringham, Heather M, Weedon, Michael N, Wheeler, Eleanor, Wood, Andrew R, Ferreira, Teresa, Weyant, Robert J, Segrè, Ayellet V, Estrada, Karol, Liang, Liming, Nemesh, James, Park, Ju-Hyun, Gustafsson, Stefan, Kilpeläinen, Tuomas O, Yang, Jian, Bouatia-Naji, Nabila, Esko, Tõnu, Feitosa, Mary F, Kutalik, Zoltán, Mangino, Massimo, Raychaudhuri, Soumya, Scherag, Andre, Smith, Albert Vernon, Welch, Ryan, Zhao, Jing Hua, Aben, Katja K, Absher, Devin M, Amin, Najaf, Dixon, Anna L, Fisher, Eva, Glazer, Nicole L, Goddard, Michael E, Heard-Costa, Nancy L, Hoesel, Volker, Hottenga, Jouke-Jan, Johansson, Åsa, Johnson, Toby, Ketkar, Shamika, Lamina, Claudia, Li, Shengxu, Moffatt, Miriam F, Myers, Richard H, Narisu, Narisu, Perry, John RB, Peters, Marjolein J, Preuss, Michael, Ripatti, Samuli, Rivadeneira, Fernando, Sandholt, Camilla, Scott, Laura J, Timpson, Nicholas J, Tyrer, Jonathan P, van Wingerden, Sophie, Watanabe, Richard M, White, Charles C, Wiklund, Fredrik, Barlassina, Christina, Chasman, Daniel I, Cooper, Matthew N, Jansson, John-Olov, Lawrence, Robert W, Pellikka, Niina, Prokopenko, Inga, Shi, Jianxin, Thiering, Elisabeth, Alavere, Helene, Alibrandi, Maria TS, Almgren, Peter, Arnold, Alice M, Aspelund, Thor, Atwood, Larry D, Balkau, Beverley, Balmforth, Anthony J, Bennett, Amanda J, Ben-Shlomo, Yoav, Bergman, Richard N, Bergmann, Sven, Biebermann, Heike, Blakemore, Alexandra IF, Boes, Tanja, Bonnycastle, Lori L, Bornstein, Stefan R, Brown, Morris J, and Buchanan, Thomas A

Subjects
Biological Sciences, Genetics, Prevention, Human Genome, Body Height, Body Mass Index, Body Size, Body Weight, Chromosome Mapping, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Obesity, Polymorphism, Single Nucleotide, White People, MAGIC, Procardis Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

Published
2010

30. Hundreds of variants clustered in genomic loci and biological pathways affect human height

Author

Lango Allen, Hana, Estrada, Karol, Lettre, Guillaume, Berndt, Sonja I, Weedon, Michael N, Rivadeneira, Fernando, Willer, Cristen J, Jackson, Anne U, Vedantam, Sailaja, Raychaudhuri, Soumya, Ferreira, Teresa, Wood, Andrew R, Weyant, Robert J, Segrè, Ayellet V, Speliotes, Elizabeth K, Wheeler, Eleanor, Soranzo, Nicole, Park, Ju-Hyun, Yang, Jian, Gudbjartsson, Daniel, Heard-Costa, Nancy L, Randall, Joshua C, Qi, Lu, Vernon Smith, Albert, Mägi, Reedik, Pastinen, Tomi, Liang, Liming, Heid, Iris M, Luan, Jian’an, Thorleifsson, Gudmar, Winkler, Thomas W, Goddard, Michael E, Sin Lo, Ken, Palmer, Cameron, Workalemahu, Tsegaselassie, Aulchenko, Yurii S, Johansson, Åsa, Carola Zillikens, M, Feitosa, Mary F, Esko, Tõnu, Johnson, Toby, Ketkar, Shamika, Kraft, Peter, Mangino, Massimo, Prokopenko, Inga, Absher, Devin, Albrecht, Eva, Ernst, Florian, Glazer, Nicole L, Hayward, Caroline, Hottenga, Jouke-Jan, Jacobs, Kevin B, Knowles, Joshua W, Kutalik, Zoltán, Monda, Keri L, Polasek, Ozren, Preuss, Michael, Rayner, Nigel W, Robertson, Neil R, Steinthorsdottir, Valgerdur, Tyrer, Jonathan P, Voight, Benjamin F, Wiklund, Fredrik, Xu, Jianfeng, Hua Zhao, Jing, Nyholt, Dale R, Pellikka, Niina, Perola, Markus, Perry, John RB, Surakka, Ida, Tammesoo, Mari-Liis, Altmaier, Elizabeth L, Amin, Najaf, Aspelund, Thor, Bhangale, Tushar, Boucher, Gabrielle, Chasman, Daniel I, Chen, Constance, Coin, Lachlan, Cooper, Matthew N, Dixon, Anna L, Gibson, Quince, Grundberg, Elin, Hao, Ke, Juhani Junttila, M, Kaplan, Lee M, Kettunen, Johannes, König, Inke R, Kwan, Tony, Lawrence, Robert W, Levinson, Douglas F, Lorentzon, Mattias, McKnight, Barbara, Morris, Andrew P, Müller, Martina, Suh Ngwa, Julius, Purcell, Shaun, Rafelt, Suzanne, Salem, Rany M, and Salvi, Erika

Subjects
Biological Sciences, Genetics, Health Sciences, Mathematical Sciences, Statistics, Human Genome, Clinical Research, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Body Height, Chromosomes, Human, Pair 3, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Metabolic Networks and Pathways, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide, General Science & Technology
Abstract

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P

Published
2010

33. Supplementary Material from Inflammatory-Related Genetic Variants in Non–Muscle-Invasive Bladder Cancer Prognosis: A Multimarker Bayesian Assessment

Author

Masson-Lecomte, Alexandra, primary, López de Maturana, Evangelina, primary, Goddard, Michael E., primary, Picornell, Antoni, primary, Rava, Marta, primary, González-Neira, Anna, primary, Márquez, Mirari, primary, Carrato, Alfredo, primary, Tardon, Adonina, primary, Lloreta, Josep, primary, Garcia-Closas, Montserrat, primary, Silverman, Debra, primary, Rothman, Nathaniel, primary, Kogevinas, Manolis, primary, Allory, Yves, primary, Chanock, Stephen J., primary, Real, Francisco X., primary, and Malats, Núria, primary

Published
2023
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34. Use of dry-matter intake recorded at multiple time periods during lactation increases the accuracy of genomic prediction for dry-matter intake and residual feed intake in dairy cattle

Author

Bolormaa, Sunduimijid, primary, Haile-Mariam, Mekonnen, additional, Marett, Leah C., additional, Miglior, Filippo, additional, Baes, Christine F., additional, Schenkel, Flavio S., additional, Connor, Erin E., additional, Manzanilla-Pech, Coralia I. V., additional, Wall, Eileen, additional, Coffey, Mike P., additional, Goddard, Michael E., additional, MacLeod, Iona M., additional, and Pryce, Jennie E., additional

Published
2023
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36. Additional file 4 of Genetic variation in histone modifications and gene expression identifies regulatory variants in the mammary gland of cattle

Author

Prowse-Wilkins, Claire P., Lopdell, Thomas J., Xiang, Ruidong, Vander Jagt, Christy J., Littlejohn, Mathew D., Chamberlain, Amanda J., and Goddard, Michael E.

Abstract

Additional file 4: Supplementary Table 6. The frequencies of the top 10 predicted transcription factor (TF) classes from the JASPAR 2018 CORE database. Supplementary Table 7. The frequencies of the top six predicted promotor element classes from the JASPAR 2018 POLII database.

Published
2023
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37. Additional file 2 of Genetic variation in histone modifications and gene expression identifies regulatory variants in the mammary gland of cattle

Author

Prowse-Wilkins, Claire P., Lopdell, Thomas J., Xiang, Ruidong, Vander Jagt, Christy J., Littlejohn, Mathew D., Chamberlain, Amanda J., and Goddard, Michael E.

Abstract

Additional file 2: Supplementary Table 2. The number of genes or exons with a heterozygous SNP (tSNP), the number of genes or exons with multiple tSNP and the number of genes or exons where the tSNP phenotypes within were significantly different (p

Published
2023
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38. Additional file 3 of Genetic variation in histone modifications and gene expression identifies regulatory variants in the mammary gland of cattle

Author

Prowse-Wilkins, Claire P., Lopdell, Thomas J., Xiang, Ruidong, Vander Jagt, Christy J., Littlejohn, Mathew D., Chamberlain, Amanda J., and Goddard, Michael E.

Abstract

Additional file 3: Supplementary Table 4. The number of peak-exon pairs with shared allele-specific QTL variants as well as the distance between peak-exon pairs and the average number of times a peak was associated with an exon and vice versa. Supplementary Table 5. The number of peak-exon pairs with shared traditional QTL as well as the distance between peak-exon pairs and the average number of times a peak was associated with an exon and vice versa.

Published
2023
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49. Interferon regulatory factor-5-dependent CD11c+ macrophages contribute to the formation of rupture–prone atherosclerotic plaques

Author

Edsfeldt, Andreas, primary, Swart, Maarten, additional, Singh, Pratibha, additional, Dib, Lea, additional, Sun, Jiangming, additional, Cole, Jennifer E, additional, Park, Inhye, additional, Al-Sharify, Dania, additional, Persson, Ana, additional, Nitulescu, Mihaela, additional, Borges, Patricia Das Neves, additional, Kassiteridi, Christina, additional, Goddard, Michael E, additional, Lee, Regent, additional, Volkov, Petr, additional, Orho-Melander, Marju, additional, Maegdefessel, Lars, additional, Nilsson, Jan, additional, Udalova, Irina, additional, Goncalves, Isabel, additional, and Monaco, Claudia, additional

Published
2022
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