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1. Leveraging single-cell ATAC-seq and RNA-seq to identify disease-critical fetal and adult brain cell types

Author

Samuel S. Kim, Buu Truong, Karthik Jagadeesh, Kushal K. Dey, Amber Z. Shen, Soumya Raychaudhuri, Manolis Kellis, and Alkes L. Price

Subjects
Science
Abstract

Abstract Prioritizing disease-critical cell types by integrating genome-wide association studies (GWAS) with functional data is a fundamental goal. Single-cell chromatin accessibility (scATAC-seq) and gene expression (scRNA-seq) have characterized cell types at high resolution, and studies integrating GWAS with scRNA-seq have shown promise, but studies integrating GWAS with scATAC-seq have been limited. Here, we identify disease-critical fetal and adult brain cell types by integrating GWAS summary statistics from 28 brain-related diseases/traits (average N = 298 K) with 3.2 million scATAC-seq and scRNA-seq profiles from 83 cell types. We identified disease-critical fetal (respectively adult) brain cell types for 22 (respectively 23) of 28 traits using scATAC-seq, and for 8 (respectively 17) of 28 traits using scRNA-seq. Significant scATAC-seq enrichments included fetal photoreceptor cells for major depressive disorder, fetal ganglion cells for BMI, fetal astrocytes for ADHD, and adult VGLUT2 excitatory neurons for schizophrenia. Our findings improve our understanding of brain-related diseases/traits and inform future analyses.

Published
2024
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2. Incorporating functional priors improves polygenic prediction accuracy in UK Biobank and 23andMe data sets

Author

Carla Márquez-Luna, Steven Gazal, Po-Ru Loh, Samuel S. Kim, Nicholas Furlotte, Adam Auton, andMe Research Team, and Alkes L. Price

Subjects
Science
Abstract

Incorporating functional information has shown promise for improving polygenic risk prediction of complex traits. Here, the authors describe polygenic prediction method LDpred-funct, and demonstrate its utility across 21 heritable traits in the UK Biobank.

Published
2021
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3. Population-specific causal disease effect sizes in functionally important regions impacted by selection

Author

Huwenbo Shi, Steven Gazal, Masahiro Kanai, Evan M. Koch, Armin P. Schoech, Katherine M. Siewert, Samuel S. Kim, Yang Luo, Tiffany Amariuta, Hailiang Huang, Yukinori Okada, Soumya Raychaudhuri, Shamil R. Sunyaev, and Alkes L. Price

Subjects
Science
Abstract

Trans-ethnic genetic correlation is significantly less than 1 for many diseases. Here, the authors stratify this correlation by genomic annotations, finding that loci whose causal disease effect sizes differ between ethnicities are likely impacted by selection, particularly positive selection.

Published
2021
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4. Improving the informativeness of Mendelian disease-derived pathogenicity scores for common disease

Author

Samuel S. Kim, Kushal K. Dey, Omer Weissbrod, Carla Márquez-Luna, Steven Gazal, and Alkes L. Price

Subjects
Science
Abstract

Pathogenicity scores are instrumental in prioritizing variants for Mendelian disease, yet their application to common disease is largely unexplored. Here, the authors assess the utility of pathogenicity scores for 41 complex traits and develop a framework to improve their informativeness for common disease.

Published
2020
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5. Evaluating the informativeness of deep learning annotations for human complex diseases

Author

Kushal K. Dey, Bryce van de Geijn, Samuel Sungil Kim, Farhad Hormozdiari, David R. Kelley, and Alkes L. Price

Subjects
Science
Abstract

Deep learning models have shown great promise in predicting regulatory effects from DNA sequence. Here the authors evaluate sequence-based epigenomic deep learning models and conclude that these models are not yet ready to inform our knowledge of human disease.

Published
2020
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6. Publisher Correction: Shared heritability and functional enrichment across six solid cancers

Author

Xia Jiang, Hilary K. Finucane, Fredrick R. Schumacher, Stephanie L. Schmit, Jonathan P. Tyrer, Younghun Han, Kyriaki Michailidou, Corina Lesseur, Karoline B. Kuchenbaecker, Joe Dennis, David V. Conti, Graham Casey, Mia M. Gaudet, Jeroen R. Huyghe, Demetrius Albanes, Melinda C. Aldrich, Angeline S. Andrew, Irene L. Andrulis, Hoda Anton-Culver, Antonis C. Antoniou, Natalia N. Antonenkova, Susanne M. Arnold, Kristan J. Aronson, Banu K. Arun, Elisa V. Bandera, Rosa B. Barkardottir, Daniel R. Barnes, Jyotsna Batra, Matthias W. Beckmann, Javier Benitez, Sara Benlloch, Andrew Berchuck, Sonja I. Berndt, Heike Bickeböller, Stephanie A. Bien, Carl Blomqvist, Stefania Boccia, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Hermann Brenner, James D. Brenton, Mark N. Brook, Joan Brunet, Hans Brunnström, Daniel D. Buchanan, Barbara Burwinkel, Ralf Butzow, Gabriella Cadoni, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Peter T. Campbell, Géraldine Cancel-Tassin, Lisa Cannon-Albright, Daniele Campa, Neil Caporaso, André L. Carvalho, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Chu Chen, David C. Christiani, Kathleen B. M. Claes, Frank Claessens, Judith Clements, J. Margriet Collée, Marcia Cruz Correa, Fergus J. Couch, Angela Cox, Julie M. Cunningham, Cezary Cybulski, Kamila Czene, Mary B. Daly, Anna deFazio, Peter Devilee, Orland Diez, Manuela Gago-Dominguez, Jenny L. Donovan, Thilo Dörk, Eric J. Duell, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Christopher K. Edlund, Digna R. Velez Edwards, Carolina Ellberg, D. Gareth Evans, Peter A. Fasching, Robert L. Ferris, Triantafillos Liloglou, Jane C. Figueiredo, Olivia Fletcher, Renée T. Fortner, Florentia Fostira, Silvia Franceschi, Eitan Friedman, Steven J. Gallinger, Patricia A. Ganz, Judy Garber, José A. García-Sáenz, Simon A. Gayther, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Ellen L. Goode, Marc T. Goodman, Gary Goodman, Kjell Grankvist, Mark H. Greene, Henrik Gronberg, Jacek Gronwald, Pascal Guénel, Niclas Håkansson, Per Hall, Ute Hamann, Freddie C. Hamdy, Robert J. Hamilton, Jochen Hampe, Aage Haugen, Florian Heitz, Rolando Herrero, Peter Hillemanns, Michael Hoffmeister, Estrid Høgdall, Yun-Chul Hong, John L. Hopper, Richard Houlston, Peter J. Hulick, David J. Hunter, David G. Huntsman, Gregory Idos, Evgeny N. Imyanitov, Sue Ann Ingles, Claudine Isaacs, Anna Jakubowska, Paul James, Mark A. Jenkins, Mattias Johansson, Mikael Johansson, Esther M. John, Amit D. Joshi, Radka Kaneva, Beth Y. Karlan, Linda E. Kelemen, Tabea Kühl, Kay-Tee Khaw, Elza Khusnutdinova, Adam S. Kibel, Lambertus A. Kiemeney, Jeri Kim, Susanne K. Kjaer, Julia A. Knight, Manolis Kogevinas, Zsofia Kote-Jarai, Stella Koutros, Vessela N. Kristensen, Jolanta Kupryjanczyk, Martin Lacko, Stephan Lam, Diether Lambrechts, Maria Teresa Landi, Philip Lazarus, Nhu D. Le, Eunjung Lee, Flavio Lejbkowicz, Heinz-Josef Lenz, Goska Leslie, Davor Lessel, Jenny Lester, Douglas A. Levine, Li Li, Christopher I. Li, Annika Lindblom, Noralane M. Lindor, Geoffrey Liu, Fotios Loupakis, Jan Lubiński, Lovise Maehle, Christiane Maier, Arto Mannermaa, Loic Le Marchand, Sara Margolin, Taymaa May, Lesley McGuffog, Alfons Meindl, Pooja Middha, Austin Miller, Roger L. Milne, Robert J. MacInnis, Francesmary Modugno, Marco Montagna, Victor Moreno, Kirsten B. Moysich, Lorelei Mucci, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, David E. Neal, Andrew R. Ness, Susan L. Neuhausen, Heli Nevanlinna, Polly A. Newcomb, Lisa F. Newcomb, Finn Cilius Nielsen, Liene Nikitina-Zake, Børge G. Nordestgaard, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Ali Amin Al Olama, Olufunmilayo I. Olopade, Andrew F. Olshan, Håkan Olsson, Ana Osorio, Hardev Pandha, Jong Y. Park, Nora Pashayan, Michael T. Parsons, Tanja Pejovic, Kathryn L. Penney, Wilbert H. M. Peters, Catherine M. Phelan, Amanda I. Phipps, Dijana Plaseska-Karanfilska, Miranda Pring, Darya Prokofyeva, Paolo Radice, Kari Stefansson, Susan J. Ramus, Leon Raskin, Gad Rennert, Hedy S. Rennert, Elizabeth J. van Rensburg, Marjorie J. Riggan, Harvey A. Risch, Angela Risch, Monique J. Roobol, Barry S. Rosenstein, Mary Anne Rossing, Kim De Ruyck, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Matthew B. Schabath, Johanna Schleutker, Marjanka K. Schmidt, V. Wendy Setiawan, Hongbing Shen, Erin M. Siegel, Weiva Sieh, Christian F. Singer, Martha L. Slattery, Karina Dalsgaard Sorensen, Melissa C. Southey, Amanda B. Spurdle, Janet L. Stanford, Victoria L. Stevens, Sebastian Stintzing, Jennifer Stone, Karin Sundfeldt, Rebecca Sutphen, Anthony J. Swerdlow, Eloiza H. Tajara, Catherine M. Tangen, Adonina Tardon, Jack A. Taylor, M. Dawn Teare, Manuel R. Teixeira, Mary Beth Terry, Kathryn L. Terry, Stephen N. Thibodeau, Mads Thomassen, Line Bjørge, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Paul A. Townsend, Ruth C. Travis, Nadine Tung, Shelley S. Tworoger, Cornelia M. Ulrich, Nawaid Usmani, Celine M. Vachon, Els Van Nieuwenhuysen, Ana Vega, Miguel Elías Aguado-Barrera, Qin Wang, Penelope M. Webb, Clarice R. Weinberg, Stephanie Weinstein, Mark C. Weissler, Jeffrey N. Weitzel, Catharine M. L. West, Emily White, Alice S. Whittemore, H-Erich Wichmann, Fredrik Wiklund, Robert Winqvist, Alicja Wolk, Penella Woll, Michael Woods, Anna H. Wu, Xifeng Wu, Drakoulis Yannoukakos, Wei Zheng, Shanbeh Zienolddiny, Argyrios Ziogas, Kristin K. Zorn, Jacqueline M. Lane, Richa Saxena, Duncan Thomas, Rayjean J. Hung, Brenda Diergaarde, James McKay, Ulrike Peters, Li Hsu, Montserrat García-Closas, Rosalind A. Eeles, Georgia Chenevix-Trench, Paul J. Brennan, Christopher A. Haiman, Jacques Simard, Douglas F. Easton, Stephen B. Gruber, Paul D. P. Pharoah, Alkes L. Price, Bogdan Pasaniuc, Christopher I. Amos, Peter Kraft, and Sara Lindström

Subjects
Science
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019
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7. Functional disease architectures reveal unique biological role of transposable elements

Author

Farhad Hormozdiari, Bryce van de Geijn, Joseph Nasser, Omer Weissbrod, Steven Gazal, Chelsea J. -T. Ju, Luke O’ Connor, Margaux L. A. Hujoel, Jesse Engreitz, Fereydoun Hormozdiari, and Alkes L. Price

Subjects
Science
Abstract

Transposable elements (TE) make up a large component of the human genome and have been shown to contribute to human diseases. Here, Hormozdiari et al. estimate the contribution of TEs to the heritability of 41 complex traits and diseases and find enrichment of SINEs in blood traits.

Published
2019
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8. Quantification of frequency-dependent genetic architectures in 25 UK Biobank traits reveals action of negative selection

Author

Armin P. Schoech, Daniel M. Jordan, Po-Ru Loh, Steven Gazal, Luke J. O’Connor, Daniel J. Balick, Pier F. Palamara, Hilary K. Finucane, Shamil R. Sunyaev, and Alkes L. Price

Subjects
Science
Abstract

Negative selection removes deleterious genetic variation, and can influence genetic architectures and evolution of complex traits. Here, the authors analyze data from 25 UK Biobank diseases and complex traits, and quantify frequency-dependent genetic architectures which suggests actions of negative selection.

Published
2019
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9. Shared heritability and functional enrichment across six solid cancers

Author

Xia Jiang, Hilary K. Finucane, Fredrick R. Schumacher, Stephanie L. Schmit, Jonathan P. Tyrer, Younghun Han, Kyriaki Michailidou, Corina Lesseur, Karoline B. Kuchenbaecker, Joe Dennis, David V. Conti, Graham Casey, Mia M. Gaudet, Jeroen R. Huyghe, Demetrius Albanes, Melinda C. Aldrich, Angeline S. Andrew, Irene L. Andrulis, Hoda Anton-Culver, Antonis C. Antoniou, Natalia N. Antonenkova, Susanne M. Arnold, Kristan J. Aronson, Banu K. Arun, Elisa V. Bandera, Rosa B. Barkardottir, Daniel R. Barnes, Jyotsna Batra, Matthias W. Beckmann, Javier Benitez, Sara Benlloch, Andrew Berchuck, Sonja I. Berndt, Heike Bickeböller, Stephanie A. Bien, Carl Blomqvist, Stefania Boccia, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Hermann Brenner, James D. Brenton, Mark N. Brook, Joan Brunet, Hans Brunnström, Daniel D. Buchanan, Barbara Burwinkel, Ralf Butzow, Gabriella Cadoni, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Peter T. Campbell, Géraldine Cancel-Tassin, Lisa Cannon-Albright, Daniele Campa, Neil Caporaso, André L. Carvalho, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Chu Chen, David C. Christiani, Kathleen B. M. Claes, Frank Claessens, Judith Clements, J. Margriet Collée, Marcia Cruz Correa, Fergus J. Couch, Angela Cox, Julie M. Cunningham, Cezary Cybulski, Kamila Czene, Mary B. Daly, Anna deFazio, Peter Devilee, Orland Diez, Manuela Gago-Dominguez, Jenny L. Donovan, Thilo Dörk, Eric J. Duell, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Christopher K. Edlund, Digna R Velez Edwards, Carolina Ellberg, D. Gareth Evans, Peter A. Fasching, Robert L. Ferris, Triantafillos Liloglou, Jane C. Figueiredo, Olivia Fletcher, Renée T. Fortner, Florentia Fostira, Silvia Franceschi, Eitan Friedman, Steven J. Gallinger, Patricia A. Ganz, Judy Garber, José A. García-Sáenz, Simon A. Gayther, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Ellen L. Goode, Marc T. Goodman, Gary Goodman, Kjell Grankvist, Mark H. Greene, Henrik Gronberg, Jacek Gronwald, Pascal Guénel, Niclas Håkansson, Per Hall, Ute Hamann, Freddie C. Hamdy, Robert J. Hamilton, Jochen Hampe, Aage Haugen, Florian Heitz, Rolando Herrero, Peter Hillemanns, Michael Hoffmeister, Estrid Høgdall, Yun-Chul Hong, John L. Hopper, Richard Houlston, Peter J. Hulick, David J. Hunter, David G. Huntsman, Gregory Idos, Evgeny N. Imyanitov, Sue Ann Ingles, Claudine Isaacs, Anna Jakubowska, Paul James, Mark A. Jenkins, Mattias Johansson, Mikael Johansson, Esther M. John, Amit D. Joshi, Radka Kaneva, Beth Y. Karlan, Linda E. Kelemen, Tabea Kühl, Kay-Tee Khaw, Elza Khusnutdinova, Adam S. Kibel, Lambertus A. Kiemeney, Jeri Kim, Susanne K. Kjaer, Julia A. Knight, Manolis Kogevinas, Zsofia Kote-Jarai, Stella Koutros, Vessela N. Kristensen, Jolanta Kupryjanczyk, Martin Lacko, Stephan Lam, Diether Lambrechts, Maria Teresa Landi, Philip Lazarus, Nhu D. Le, Eunjung Lee, Flavio Lejbkowicz, Heinz-Josef Lenz, Goska Leslie, Davor Lessel, Jenny Lester, Douglas A. Levine, Li Li, Christopher I. Li, Annika Lindblom, Noralane M. Lindor, Geoffrey Liu, Fotios Loupakis, Jan Lubiński, Lovise Maehle, Christiane Maier, Arto Mannermaa, Loic Le Marchand, Sara Margolin, Taymaa May, Lesley McGuffog, Alfons Meindl, Pooja Middha, Austin Miller, Roger L. Milne, Robert J. MacInnis, Francesmary Modugno, Marco Montagna, Victor Moreno, Kirsten B. Moysich, Lorelei Mucci, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, David E. Neal, Andrew R. Ness, Susan L. Neuhausen, Heli Nevanlinna, Polly A. Newcomb, Lisa F. Newcomb, Finn Cilius Nielsen, Liene Nikitina-Zake, Børge G. Nordestgaard, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Ali Amin Al Olama, Olufunmilayo I. Olopade, Andrew F. Olshan, Håkan Olsson, Ana Osorio, Hardev Pandha, Jong Y. Park, Nora Pashayan, Michael T. Parsons, Tanja Pejovic, Kathryn L. Penney, Wilbert H M. Peters, Catherine M. Phelan, Amanda I. Phipps, Dijana Plaseska-Karanfilska, Miranda Pring, Darya Prokofyeva, Paolo Radice, Kari Stefansson, Susan J. Ramus, Leon Raskin, Gad Rennert, Hedy S. Rennert, Elizabeth J. van Rensburg, Marjorie J. Riggan, Harvey A. Risch, Angela Risch, Monique J. Roobol, Barry S. Rosenstein, Mary Anne Rossing, Kim De Ruyck, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Matthew B. Schabath, Johanna Schleutker, Marjanka K. Schmidt, V. Wendy Setiawan, Hongbing Shen, Erin M. Siegel, Weiva Sieh, Christian F. Singer, Martha L. Slattery, Karina Dalsgaard Sorensen, Melissa C. Southey, Amanda B. Spurdle, Janet L. Stanford, Victoria L. Stevens, Sebastian Stintzing, Jennifer Stone, Karin Sundfeldt, Rebecca Sutphen, Anthony J. Swerdlow, Eloiza H. Tajara, Catherine M. Tangen, Adonina Tardon, Jack A. Taylor, M. Dawn Teare, Manuel R. Teixeira, Mary Beth Terry, Kathryn L. Terry, Stephen N. Thibodeau, Mads Thomassen, Line Bjørge, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Paul A. Townsend, Ruth C. Travis, Nadine Tung, Shelley S. Tworoger, Cornelia M. Ulrich, Nawaid Usmani, Celine M. Vachon, Els Van Nieuwenhuysen, Ana Vega, Miguel Elías Aguado-Barrera, Qin Wang, Penelope M. Webb, Clarice R. Weinberg, Stephanie Weinstein, Mark C. Weissler, Jeffrey N. Weitzel, Catharine M. L. West, Emily White, Alice S. Whittemore, H-Erich Wichmann, Fredrik Wiklund, Robert Winqvist, Alicja Wolk, Penella Woll, Michael Woods, Anna H. Wu, Xifeng Wu, Drakoulis Yannoukakos, Wei Zheng, Shanbeh Zienolddiny, Argyrios Ziogas, Kristin K. Zorn, Jacqueline M. Lane, Richa Saxena, Duncan Thomas, Rayjean J. Hung, Brenda Diergaarde, James McKay, Ulrike Peters, Li Hsu, Montserrat García-Closas, Rosalind A. Eeles, Georgia Chenevix-Trench, Paul J. Brennan, Christopher A. Haiman, Jacques Simard, Douglas F. Easton, Stephen B. Gruber, Paul D. P. Pharoah, Alkes L. Price, Bogdan Pasaniuc, Christopher I. Amos, Peter Kraft, and Sara Lindström

Subjects
Science
Abstract

Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

Published
2019
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10. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

Author

Alexander Gusev, Huwenbo Shi, Gleb Kichaev, Mark Pomerantz, Fugen Li, Henry W. Long, Sue A. Ingles, Rick A. Kittles, Sara S. Strom, Benjamin A. Rybicki, Barbara Nemesure, William B. Isaacs, Wei Zheng, Curtis A. Pettaway, Edward D. Yeboah, Yao Tettey, Richard B. Biritwum, Andrew A. Adjei, Evelyn Tay, Ann Truelove, Shelley Niwa, Anand P. Chokkalingam, Esther M. John, Adam B. Murphy, Lisa B. Signorello, John Carpten, M. Cristina Leske, Suh-Yuh Wu, Anslem J. M. Hennis, Christine Neslund-Dudas, Ann W. Hsing, Lisa Chu, Phyllis J. Goodman, Eric A. Klein, John S. Witte, Graham Casey, Sam Kaggwa, Michael B. Cook, Daniel O. Stram, William J. Blot, Rosalind A. Eeles, Douglas Easton, ZSofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch, Kenneth Muir, Graham G. Giles, Melissa C. Southey, Liesel M. Fitzgerald, Henrik Gronberg, Fredrik Wiklund, Markus Aly, Brian E. Henderson, Johanna Schleutker, Tiina Wahlfors, Teuvo L. J. Tammela, Børge G. Nordestgaard, Tim J. Key, Ruth C. Travis, David E. Neal, Jenny L. Donovan, Freddie C. Hamdy, Paul Pharoah, Nora Pashayan, Kay-Tee Khaw, Janet L. Stanford, Stephen N. Thibodeau, Shannon K. McDonnell, Daniel J. Schaid, Christiane Maier, Walther Vogel, Manuel Luedeke, Kathleen Herkommer, Adam S. Kibel, Cezary Cybulski, Dominika Wokolorczyk, Wojciech Kluzniak, Lisa Cannon-Albright, Craig Teerlink, Hermann Brenner, Aida K. Dieffenbach, Volker Arndt, Jong Y. Park, Thomas A. Sellers, Hui-Yi Lin, Chavdar Slavov, Radka Kaneva, Vanio Mitev, Jyotsna Batra, Amanda Spurdle, Judith A. Clements, Manuel R. Teixeira, Hardev Pandha, Agnieszka Michael, Paula Paulo, Sofia Maia, Andrzej Kierzek, The PRACTICAL consortium, David V. Conti, Demetrius Albanes, Christine Berg, Sonja I. Berndt, Daniele Campa, E. David Crawford, W. Ryan Diver, Susan M. Gapstur, J. Michael Gaziano, Edward Giovannucci, Robert Hoover, David J. Hunter, Mattias Johansson, Peter Kraft, Loic Le Marchand, Sara Lindström, Carmen Navarro, Kim Overvad, Elio Riboli, Afshan Siddiq, Victoria L. Stevens, Dimitrios Trichopoulos, Paolo Vineis, Meredith Yeager, Gosia Trynka, Soumya Raychaudhuri, Frederick R. Schumacher, Alkes L. Price, Matthew L. Freedman, Christopher A. Haiman, and Bogdan Pasaniuc

Subjects
Science
Abstract

Over one hundred loci have been identified to be associated with the familial risk of prostate cancer but the functional effects are poorly understood. Here the authors use single-nucleotide variant and epigentic data to show an underlying genetic architecture marked by histone modification.

Published
2016
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11. Population-specific causal disease effect sizes in functionally important regions impacted by selection

Author

Katherine M. Siewert, Yukinori Okada, Hailiang Huang, Soumya Raychaudhuri, Evan M. Koch, Samuel S. Kim, Yang Luo, Huwenbo Shi, Armin P. Schoech, Alkes L. Price, Steven Gazal, Masahiro Kanai, Tiffany Amariuta, and Shamil R. Sunyaev

Subjects
0301 basic medicine, Linkage disequilibrium, Science, General Physics and Astronomy, Evolutionary biology, Single-nucleotide polymorphism, Disease, Biology, Polymorphism, Single Nucleotide, Genome-wide association studies, Genetic correlation, Linkage Disequilibrium, White People, Article, General Biochemistry, Genetics and Molecular Biology, Correlation, 03 medical and health sciences, 0302 clinical medicine, Asian People, Population specific, Humans, Selection, Genetic, Gene, Selection (genetic algorithm), Statistic, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Models, Genetic, Medical genetics, Genomics, General Chemistry, Background selection, Genetics, Population, 030104 developmental biology, Haplotypes, Heritable quantitative trait, Algorithms, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Many diseases exhibit population-specific causal effect sizes with trans-ethnic genetic correlations significantly less than 1, limiting trans-ethnic polygenic risk prediction. We develop a new method, S-LDXR, for stratifying squared trans-ethnic genetic correlation across genomic annotations, and apply S-LDXR to genome-wide summary statistics for 31 diseases and complex traits in East Asians (average N = 90K) and Europeans (average N = 267K) with an average trans-ethnic genetic correlation of 0.85. We determine that squared trans-ethnic genetic correlation is 0.82× (s.e. 0.01) depleted in the top quintile of background selection statistic, implying more population-specific causal effect sizes. Accordingly, causal effect sizes are more population-specific in functionally important regions, including conserved and regulatory regions. In regions surrounding specifically expressed genes, causal effect sizes are most population-specific for skin and immune genes, and least population-specific for brain genes. Our results could potentially be explained by stronger gene-environment interaction at loci impacted by selection, particularly positive selection., Trans-ethnic genetic correlation is significantly less than 1 for many diseases. Here, the authors stratify this correlation by genomic annotations, finding that loci whose causal disease effect sizes differ between ethnicities are likely impacted by selection, particularly positive selection.

Published
2021
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12. Improving the informativeness of Mendelian disease-derived pathogenicity scores for common disease

Author

Carla Marquez-Luna, Kushal K. Dey, Omer Weissbrod, Alkes L. Price, Steven Gazal, and Samuel S. Kim

Subjects
0301 basic medicine, Candidate gene, Linkage disequilibrium, Statistical methods, Science, Mutation, Missense, General Physics and Astronomy, Single-nucleotide polymorphism, Biology, Mendelian disease, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Article, General Biochemistry, Genetics and Molecular Biology, Machine Learning, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Humans, Genetic Predisposition to Disease, Alleles, Genetics, Multidisciplinary, Genetic Diseases, Inborn, Functional genomics, General Chemistry, Mendelian Randomization Analysis, Heritability, Pathogenicity, Regression, 030104 developmental biology, Mendelian inheritance, symbols, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Despite considerable progress on pathogenicity scores prioritizing variants for Mendelian disease, little is known about the utility of these scores for common disease. Here, we assess the informativeness of Mendelian disease-derived pathogenicity scores for common disease and improve upon existing scores. We first apply stratified linkage disequilibrium (LD) score regression to evaluate published pathogenicity scores across 41 common diseases and complex traits (average N = 320K). Several of the resulting annotations are informative for common disease, even after conditioning on a broad set of functional annotations. We then improve upon published pathogenicity scores by developing AnnotBoost, a machine learning framework to impute and denoise pathogenicity scores using a broad set of functional annotations. AnnotBoost substantially increases the informativeness for common disease of both previously uninformative and previously informative pathogenicity scores, implying that Mendelian and common disease variants share similar properties. The boosted scores also produce improvements in heritability model fit and in classifying disease-associated, fine-mapped SNPs. Our boosted scores may improve fine-mapping and candidate gene discovery for common disease., Pathogenicity scores are instrumental in prioritizing variants for Mendelian disease, yet their application to common disease is largely unexplored. Here, the authors assess the utility of pathogenicity scores for 41 complex traits and develop a framework to improve their informativeness for common disease.

Published
2020
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13. Evaluating the informativeness of deep learning annotations for human complex diseases

Author

Samuel S. Kim, Bryce van de Geijn, Alkes L. Price, Farhad Hormozdiari, David R. Kelley, and Kushal K. Dey

Subjects
0301 basic medicine, Autoimmune diseases, General Physics and Astronomy, Genome-wide association study, Disease, Linkage Disequilibrium, Histones, 0302 clinical medicine, lcsh:Science, 0303 health sciences, Multidisciplinary, Regression, 3. Good health, Phenotype, Molecular Sequence Annotation, Science, Single-nucleotide polymorphism, Computational biology, Biology, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Annotation, 03 medical and health sciences, Deep Learning, Machine learning, Humans, SNP, Genetic Predisposition to Disease, Allele, Set (psychology), Alleles, 030304 developmental biology, Models, Genetic, Genome, Human, business.industry, Deep learning, General Chemistry, Heritability, 030104 developmental biology, Mutagenesis, lcsh:Q, Artificial intelligence, business, 030217 neurology & neurosurgery, Coding (social sciences), Genome-Wide Association Study
Abstract

Deep learning models have shown great promise in predicting regulatory effects from DNA sequence, but their informativeness for human complex diseases is not fully understood. Here, we evaluate genome-wide SNP annotations from two previous deep learning models, DeepSEA and Basenji, by applying stratified LD score regression to 41 diseases and traits (average N = 320K), conditioning on a broad set of coding, conserved and regulatory annotations. We aggregated annotations across all (respectively blood or brain) tissues/cell-types in meta-analyses across all (respectively 11 blood or 8 brain) traits. The annotations were highly enriched for disease heritability, but produced only limited conditionally significant results: non-tissue-specific and brain-specific Basenji-H3K4me3 for all traits and brain traits respectively. We conclude that deep learning models have yet to achieve their full potential to provide considerable unique information for complex disease, and that their conditional informativeness for disease cannot be inferred from their accuracy in predicting regulatory annotations., Deep learning models have shown great promise in predicting regulatory effects from DNA sequence. Here the authors evaluate sequence-based epigenomic deep learning models and conclude that these models are not yet ready to inform our knowledge of human disease.

Published
2020
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14. Publisher Correction: Shared heritability and functional enrichment across six solid cancers

Author

Karina Dalsgaard Sørensen, Mattias Johansson, Manjeet K. Bolla, Kay-Tee Khaw, Carl Blomqvist, Joan Brunet, Robert L. Ferris, Graham G. Giles, Ruth C. Travis, Philip Lazarus, Stephan Lam, Stella Koutros, Michael Hoffmeister, Liene Nikitina-Zake, Adonina Tardón, Christopher I. Amos, Emmanouil Saloustros, Christopher K. Edlund, Jacqueline M. Lane, Ana Osorio, Dijana Plaseska-Karanfilska, Catherine M. Tangen, Brenda Diergaarde, Mark C. Weissler, Diana Eccles, Per Hall, Mark H. Greene, Pascal Guénel, Amanda B. Spurdle, Marco Montagna, Sara Margolin, Gary E. Goodman, Irene L. Andrulis, Hongbing Shen, Barry S. Rosenstein, Hedy S. Rennert, Julie M. Cunningham, Paul Brennan, Jeroen R. Huyghe, Andrew T. Chan, Henrik Grönberg, Orland Diez, Hiltrud Brauch, Eunjung Lee, Trinidad Caldés, V. Wendy Setiawan, Matthias W. Beckmann, Angeline S. Andrew, Pooja Middha, Shelley S. Tworoger, Maria Teresa Landi, Alison M. Dunning, Jenny Lester, Angela Cox, Daniel R. Barnes, Jong Y. Park, Renée T. Fortner, Peter Kraft, Florentia Fostira, Mary Beth Terry, Jenny Chang-Claude, Tabea Kühl, Dale P. Sandler, Jeri Kim, Sue A. Ingles, Andy R Ness, Younghun Han, Marc Tischkowitz, Evgeny N. Imyanitov, Annika Lindblom, Ralf Bützow, Austin Miller, Kamila Czene, Jochen Hampe, Robert J. Hamilton, José A. García-Sáenz, Kenneth Muir, Wei Zheng, Gad Rennert, Johanna Schleutker, Mary Anne Rossing, Thilo Dörk, Andrew Berchuck, Angela Risch, Jyotsna Batra, Michael O. Woods, Julia A. Knight, Elinor J. Sawyer, Kim De Ruyck, Douglas F. Easton, Jeffrey N. Weitzel, Anna H. Wu, Børge G. Nordestgaard, Francesmary Modugno, Alkes L. Price, Douglas A. Levine, Lorelei A. Mucci, John L. Hopper, Davor Lessel, Javier Benitez, Richard S. Houlston, Diana Torres, Corina Lesseur, Arto Mannermaa, Daniel D. Buchanan, Mary B. Daly, Xifeng Wu, Matthew B. Schabath, Barbara Burwinkel, Bogdan Pasaniuc, Graham Casey, Peter A. Fasching, David G. Huntsman, Mads Thomassen, Manuela Gago-Dominguez, Lesley McGuffog, Christian F. Singer, Patricia A. Ganz, Manolis Kogevinas, Andrew F. Olshan, André Lopes Carvalho, Polly A. Newcomb, Banu Arun, Sonja I. Berndt, Niclas Håkansson, Leon Raskin, Marc T. Goodman, M. Dawn Teare, Hoda Anton-Culver, Fergus J. Couch, Christopher I. Li, Peter Devilee, Kristin K. Zorn, Neil E. Caporaso, Chu Chen, Kenneth Offit, Eitan Friedman, Natalia Antonenkova, Ute Hamann, Karin Sundfeldt, Stephanie A. Bien, Weiva Sieh, Rosalind A. Eeles, Claudine Isaacs, Maria A. Caligo, Nhu D. Le, Ulrike Peters, Triantafillos Liloglou, Stefania Boccia, Jacques Simard, Melissa C. Southey, Kathleen Claes, Darya Prokofyeva, Heike Bickeböller, Argyrios Ziogas, Sebastian Stintzing, Rayjean J. Hung, Carolina Ellberg, Rolando Herrero, Jennifer Stone, David C. Christiani, Mikael Johansson, Wilbert H.M. Peters, Montserrat Garcia-Closas, Jan Lubinski, Marcia Cruz Correa, Gabriella Cadoni, Rebecca Sutphen, Cornelia M. Ulrich, Paul A. Townsend, Qin Wang, Li Li, Nadine Tung, Ellen L. Goode, Silvia Franceschi, Lisa A. Cannon-Albright, Finn Cilius Nielsen, Stephanie L. Schmit, Antonis C. Antoniou, Clarice R. Weinberg, Kyriaki Michailidou, Susanne M. Arnold, Li Hsu, Natalia Bogdanova, Victor Moreno, Paolo Radice, Peter Hillemanns, Eloiza H. Tajara, Olufunmilayo I. Olopade, Stephen B. Gruber, Heli Nevanlinna, Kari Stefansson, Yun-Chul Hong, Amit Joshi, Emily White, Peter J. Hulick, Aage Haugen, Sara Benlloch, Mark A. Jenkins, Xia Jiang, Peter T. Campbell, Jack A. Taylor, Christopher A. Haiman, Jenny L Donovan, Roger L. Milne, Stephen J. Chanock, Judy Garber, Stig E. Bojesen, Taymaa May, David E. Neal, Kirsten B. Moysich, Jane C. Figueiredo, Alfons Meindl, Georgia Chenevix-Trench, Frank Claessens, Melinda C. Aldrich, Gregory Idos, Robert L. Nussbaum, Robert Winqvist, Tanja Pejovic, H-Erich Wichmann, Diether Lambrechts, Eric J. Duell, Demetrius Albanes, Drakoulis Yannoukakos, Kathryn L. Penney, Loic Le Marchand, Florian Heitz, Beth Y. Karlan, Lovise Maehle, Fotios Loupakis, Ana Vega, Zsofia Kote-Jarai, Marjorie J. Riggan, Stephen N. Thibodeau, Fredrik Wiklund, Steven Gallinger, Hans Brunnström, Geoffrey Liu, Duncan Thomas, Kathryn L. Terry, Els Van Nieuwenhuysen, Anthony J. Swerdlow, Miguel E. Aguado-Barrera, Nawaid Usmani, Mia M. Gaudet, David J. Hunter, Estrid Høgdall, Kristan J. Aronson, Vessela N. Kristensen, Line Bjørge, Amanda E. Toland, Anna Marie Mulligan, Noralane M. Lindor, Flavio Lejbkowicz, Jonathan Tyrer, James D. Brenton, Alice S. Whittemore, Catharine M L West, Goska Leslie, Jacek Gronwald, Martha L. Slattery, Christiane Maier, Radka Kaneva, Joe Dennis, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Erin M. Siegel, Paul A. James, Penella J. Woll, Catherine M. Phelan, Susan J. Ramus, Olivia Fletcher, Hermann Brenner, Geraldine Cancel-Tassin, Marjanka K. Schmidt, D. Gareth Evans, Manuel R. Teixeira, Amanda I. Phipps, Jolanta Kupryjanczyk, Penelope M. Webb, James McKay, Shanbeh Zienolddiny, Sara Lindström, Lambertus A. Kiemeney, Celine M. Vachon, Ali Amin Al Olama, Edith Olah, Andrew K. Godwin, Victoria L. Stevens, Mark N. Brook, Fredrick R. Schumacher, Digna R. Velez Edwards, Lisa F. Newcomb, Michael T. Parsons, David V. Conti, J. Margriet Collée, Rosa B. Barkardottir, Simon A. Gayther, Miranda Pring, Harvey A. Risch, Karoline Kuchenbaecker, Martin Lacko, Judith A. Clements, Mark S. Goldberg, Adam S. Kibel, Robert J. MacInnis, Richa Saxena, Heinz-Josef Lenz, Linda E. Kelemen, Stephanie J. Weinstein, Elisa V. Bandera, Freddie C. Hamdy, Håkan Olsson, Cezary Cybulski, Katherine L. Nathanson, Anna deFazio, Ian G. Campbell, Nora Pashayan, Hilary K. Finucane, Hardev Pandha, Susan L. Neuhausen, Alicja Wolk, Elizabeth J. van Rensburg, Esther M. John, Daniele Campa, Kjell Grankvist, Janet L. Stanford, Miriam Dwek, Susanne K. Kjaer, Monique J. Roobol, and Elza Khusnutdinova

Subjects
Genetics, 0303 health sciences, Multidisciplinary, business.industry, Published Erratum, Science, MEDLINE, General Physics and Astronomy, General Chemistry, Heritability, General Biochemistry, Genetics and Molecular Biology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Medicine, lcsh:Q, lcsh:Science, business, solid cancers, 030304 developmental biology
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019
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15. Quantification of frequency-dependent genetic architectures in 25 UK Biobank traits reveals action of negative selection

Author

Steven Gazal, Po-Ru Loh, Daniel M. Jordan, Alkes L. Price, Armin P. Schoech, Daniel J. Balick, Pier Francesco Palamara, Luke J. O’Connor, Hilary K. Finucane, and Shamil R. Sunyaev

Subjects
0301 basic medicine, Genotype, Science, General Physics and Astronomy, 02 engineering and technology, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Negative selection, Quantitative Trait, Heritable, Gene Frequency, Genetic variation, Humans, Allele, Selection, Genetic, lcsh:Science, Allele frequency, Selection (genetic algorithm), Alleles, Biological Specimen Banks, Multidisciplinary, Models, Genetic, General Chemistry, 021001 nanoscience & nanotechnology, United Kingdom, Minor allele frequency, 030104 developmental biology, Evolutionary biology, Trait, lcsh:Q, 0210 nano-technology, Algorithms, Genome-Wide Association Study
Abstract

Understanding the role of rare variants is important in elucidating the genetic basis of human disease. Negative selection can cause rare variants to have larger per-allele effect sizes than common variants. Here, we develop a method to estimate the minor allele frequency (MAF) dependence of SNP effect sizes. We use a model in which per-allele effect sizes have variance proportional to [p(1 − p)]α, where p is the MAF and negative values of α imply larger effect sizes for rare variants. We estimate α for 25 UK Biobank diseases and complex traits. All traits produce negative α estimates, with best-fit mean of –0.38 (s.e. 0.02) across traits. Despite larger rare variant effect sizes, rare variants (MAF, Negative selection removes deleterious genetic variation, and can influence genetic architectures and evolution of complex traits. Here, the authors analyze data from 25 UK Biobank diseases and complex traits, and quantify frequency-dependent genetic architectures which suggests actions of negative selection.

Published
2018

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