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1. A genomic mutational constraint map using variation in 76,156 human genomes

Author

Chen, Siwei, Francioli, Laurent C., Goodrich, Julia K., Collins, Ryan L., Kanai, Masahiro, Wang, Qingbo, Alföldi, Jessica, Watts, Nicholas A., Vittal, Christopher, Gauthier, Laura D., Poterba, Timothy, Wilson, Michael W., Tarasova, Yekaterina, Phu, William, Grant, Riley, Yohannes, Mary T., Koenig, Zan, Farjoun, Yossi, Banks, Eric, Donnelly, Stacey, Gabriel, Stacey, Gupta, Namrata, Ferriera, Steven, Tolonen, Charlotte, Novod, Sam, Bergelson, Louis, Roazen, David, Ruano-Rubio, Valentin, Covarrubias, Miguel, Llanwarne, Christopher, Petrillo, Nikelle, Wade, Gordon, Jeandet, Thibault, Munshi, Ruchi, Tibbetts, Kathleen, O’Donnell-Luria, Anne, Solomonson, Matthew, Seed, Cotton, Martin, Alicia R., Talkowski, Michael E., Rehm, Heidi L., Daly, Mark J., Tiao, Grace, Neale, Benjamin M., MacArthur, Daniel G., and Karczewski, Konrad J.

Published
2024
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2. Rare coding variants in ten genes confer substantial risk for schizophrenia.

Author

Singh, Tarjinder, Poterba, Timothy, Curtis, David, Akil, Huda, Al Eissa, Mariam, Barchas, Jack D, Bass, Nicholas, Bigdeli, Tim B, Breen, Gerome, Bromet, Evelyn J, Buckley, Peter F, Bunney, William E, Bybjerg-Grauholm, Jonas, Byerley, William F, Chapman, Sinéad B, Chen, Wei J, Churchhouse, Claire, Craddock, Nicholas, Cusick, Caroline M, DeLisi, Lynn, Dodge, Sheila, Escamilla, Michael A, Eskelinen, Saana, Fanous, Ayman H, Faraone, Stephen V, Fiorentino, Alessia, Francioli, Laurent, Gabriel, Stacey B, Gage, Diane, Gagliano Taliun, Sarah A, Ganna, Andrea, Genovese, Giulio, Glahn, David C, Grove, Jakob, Hall, Mei-Hua, Hämäläinen, Eija, Heyne, Henrike O, Holi, Matti, Hougaard, David M, Howrigan, Daniel P, Huang, Hailiang, Hwu, Hai-Gwo, Kahn, René S, Kang, Hyun Min, Karczewski, Konrad J, Kirov, George, Knowles, James A, Lee, Francis S, Lehrer, Douglas S, Lescai, Francesco, Malaspina, Dolores, Marder, Stephen R, McCarroll, Steven A, McIntosh, Andrew M, Medeiros, Helena, Milani, Lili, Morley, Christopher P, Morris, Derek W, Mortensen, Preben Bo, Myers, Richard M, Nordentoft, Merete, O'Brien, Niamh L, Olivares, Ana Maria, Ongur, Dost, Ouwehand, Willem H, Palmer, Duncan S, Paunio, Tiina, Quested, Digby, Rapaport, Mark H, Rees, Elliott, Rollins, Brandi, Satterstrom, F Kyle, Schatzberg, Alan, Scolnick, Edward, Scott, Laura J, Sharp, Sally I, Sklar, Pamela, Smoller, Jordan W, Sobell, Janet L, Solomonson, Matthew, Stahl, Eli A, Stevens, Christine R, Suvisaari, Jaana, Tiao, Grace, Watson, Stanley J, Watts, Nicholas A, Blackwood, Douglas H, Børglum, Anders D, Cohen, Bruce M, Corvin, Aiden P, Esko, Tõnu, Freimer, Nelson B, Glatt, Stephen J, Hultman, Christina M, McQuillin, Andrew, Palotie, Aarno, Pato, Carlos N, Pato, Michele T, Pulver, Ann E, and St Clair, David

Subjects
Humans, Genetic Predisposition to Disease, Receptors, N-Methyl-D-Aspartate, Case-Control Studies, Schizophrenia, Mutation, Exome, Neurodevelopmental Disorders, Human Genome, Biotechnology, Mental Health, Neurosciences, Brain Disorders, Genetics, Serious Mental Illness, Aetiology, 2.1 Biological and endogenous factors, Mental health, Neurological, General Science & Technology
Abstract

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, P

Published
2022

4. Author Correction: A genomic mutational constraint map using variation in 76,156 human genomes

Author

Chen, Siwei, Francioli, Laurent C., Goodrich, Julia K., Collins, Ryan L., Kanai, Masahiro, Wang, Qingbo, Alföldi, Jessica, Watts, Nicholas A., Vittal, Christopher, Gauthier, Laura D., Poterba, Timothy, Wilson, Michael W., Tarasova, Yekaterina, Phu, William, Grant, Riley, Yohannes, Mary T., Koenig, Zan, Farjoun, Yossi, Banks, Eric, Donnelly, Stacey, Gabriel, Stacey, Gupta, Namrata, Ferriera, Steven, Tolonen, Charlotte, Novod, Sam, Bergelson, Louis, Roazen, David, Ruano-Rubio, Valentin, Covarrubias, Miguel, Llanwarne, Christopher, Petrillo, Nikelle, Wade, Gordon, Jeandet, Thibault, Munshi, Ruchi, Tibbetts, Kathleen, O’Donnell-Luria, Anne, Solomonson, Matthew, Seed, Cotton, Martin, Alicia R., Talkowski, Michael E., Rehm, Heidi L., Daly, Mark J., Tiao, Grace, Neale, Benjamin M., MacArthur, Daniel G., and Karczewski, Konrad J.

Published
2024
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5. Publisher Correction: Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

Author

Zekavat, Seyedeh M, Ruotsalainen, Sanni, Handsaker, Robert E, Alver, Maris, Bloom, Jonathan, Poterba, Timothy, Seed, Cotton, Ernst, Jason, Chaffin, Mark, Engreitz, Jesse, Peloso, Gina M, Manichaikul, Ani, Yang, Chaojie, Ryan, Kathleen A, Fu, Mao, Johnson, W Craig, Tsai, Michael, Budoff, Matthew, Vasan, Ramachandran S, Cupples, L Adrienne, Rotter, Jerome I, Rich, Stephen S, Post, Wendy, Mitchell, Braxton D, Correa, Adolfo, Metspalu, Andres, Wilson, James G, Salomaa, Veikko, Kellis, Manolis, Daly, Mark J, Neale, Benjamin M, McCarroll, Steven, Surakka, Ida, Esko, Tonu, Ganna, Andrea, Ripatti, Samuli, Kathiresan, Sekar, Natarajan, Pradeep, and NHLBI TOPMed Lipids Working Group

Subjects
NHLBI TOPMed Lipids Working Group
Abstract

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

Published
2020

6. Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Author

Consortium, Cross-Disorder Group of the Psychiatric Genomics, Lee, Phil H, Anttila, Verneri, Won, Hyejung, Feng, Yen-Chen A, Rosenthal, Jacob, Zhu, Zhaozhong, Tucker-Drob, Elliot M, Nivard, Michel G, Grotzinger, Andrew D, Posthuma, Danielle, Wang, Meg M-J, Yu, Dongmei, Stahl, Eli A, Walters, Raymond K, Anney, Richard JL, Duncan, Laramie E, Ge, Tian, Adolfsson, Rolf, Banaschewski, Tobias, Belangero, Sintia, Cook, Edwin H, Coppola, Giovanni, Derks, Eske M, Hoekstra, Pieter J, Kaprio, Jaakko, Keski-Rahkonen, Anna, Kirov, George, Kranzler, Henry R, Luykx, Jurjen J, Rohde, Luis A, Zai, Clement C, Agerbo, Esben, Arranz, MJ, Asherson, Philip, Bækvad-Hansen, Marie, Baldursson, Gísli, Bellgrove, Mark, Belliveau, Richard A, Buitelaar, Jan, Burton, Christie L, Bybjerg-Grauholm, Jonas, Casas, Miquel, Cerrato, Felecia, Chambert, Kimberly, Churchhouse, Claire, Cormand, Bru, Crosbie, Jennifer, Dalsgaard, Søren, Demontis, Ditte, Doyle, Alysa E, Dumont, Ashley, Elia, Josephine, Grove, Jakob, Gudmundsson, Olafur O, Haavik, Jan, Hakonarson, Hakon, Hansen, Christine S, Hartman, Catharina A, Hawi, Ziarih, Hervás, Amaia, Hougaard, David M, Howrigan, Daniel P, Huang, Hailiang, Kuntsi, Jonna, Langley, Kate, Lesch, Klaus-Peter, Leung, Patrick WL, Loo, Sandra K, Martin, Joanna, Martin, Alicia R, McGough, James J, Medland, Sarah E, Moran, Jennifer L, Mors, Ole, Mortensen, Preben B, Oades, Robert D, Palmer, Duncan S, Pedersen, Carsten B, Pedersen, Marianne G, Peters, Triinu, Poterba, Timothy, Poulsen, Jesper B, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Ribasés, Marta, Rothenberger, Aribert, Rovira, Paula, Sánchez-Mora, Cristina, Satterstrom, F Kyle, Schachar, Russell, Artigas, Maria Soler, Steinberg, Stacy, Stefansson, Hreinn, Turley, Patrick, Walters, G Bragi, Team, 23andMe Research, Werge, Thomas, Zayats, Tetyana, and Arking, Dan E

Subjects
Neurosciences, Serious Mental Illness, Human Genome, Schizophrenia, Intellectual and Developmental Disabilities (IDD), Brain Disorders, Genetics, Pediatric, Mental Health, Aetiology, 2.1 Biological and endogenous factors, Mental health, Genetic Pleiotropy, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mental Disorders, Neurogenesis, Quantitative Trait Loci, Cross-Disorder Group of the Psychiatric Genomics Consortium. Electronic address: plee0@mgh.harvard.edu, Cross-Disorder Group of the Psychiatric Genomics Consortium, GWAS, Psychiatric genetics, cross-disorder genetics, functional genomics, gene expression, genetic architecture, genetic correlation, neurodevelopment, pleiotropy, psychiatric disorders, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.

Published
2019

7. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.

Author

Demontis, Ditte, Walters, Raymond K, Martin, Joanna, Mattheisen, Manuel, Als, Thomas D, Agerbo, Esben, Baldursson, Gísli, Belliveau, Rich, Bybjerg-Grauholm, Jonas, Bækvad-Hansen, Marie, Cerrato, Felecia, Chambert, Kimberly, Churchhouse, Claire, Dumont, Ashley, Eriksson, Nicholas, Gandal, Michael, Goldstein, Jacqueline I, Grasby, Katrina L, Grove, Jakob, Gudmundsson, Olafur O, Hansen, Christine S, Hauberg, Mads Engel, Hollegaard, Mads V, Howrigan, Daniel P, Huang, Hailiang, Maller, Julian B, Martin, Alicia R, Martin, Nicholas G, Moran, Jennifer, Pallesen, Jonatan, Palmer, Duncan S, Pedersen, Carsten Bøcker, Pedersen, Marianne Giørtz, Poterba, Timothy, Poulsen, Jesper Buchhave, Ripke, Stephan, Robinson, Elise B, Satterstrom, F Kyle, Stefansson, Hreinn, Stevens, Christine, Turley, Patrick, Walters, G Bragi, Won, Hyejung, Wright, Margaret J, ADHD Working Group of the Psychiatric Genomics Consortium (PGC), Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium, 23andMe Research Team, Andreassen, Ole A, Asherson, Philip, Burton, Christie L, Boomsma, Dorret I, Cormand, Bru, Dalsgaard, Søren, Franke, Barbara, Gelernter, Joel, Geschwind, Daniel, Hakonarson, Hakon, Haavik, Jan, Kranzler, Henry R, Kuntsi, Jonna, Langley, Kate, Lesch, Klaus-Peter, Middeldorp, Christel, Reif, Andreas, Rohde, Luis Augusto, Roussos, Panos, Schachar, Russell, Sklar, Pamela, Sonuga-Barke, Edmund JS, Sullivan, Patrick F, Thapar, Anita, Tung, Joyce Y, Waldman, Irwin D, Medland, Sarah E, Stefansson, Kari, Nordentoft, Merete, Hougaard, David M, Werge, Thomas, Mors, Ole, Mortensen, Preben Bo, Daly, Mark J, Faraone, Stephen V, Børglum, Anders D, and Neale, Benjamin M

Subjects
ADHD Working Group of the Psychiatric Genomics Consortium, Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium, 23andMe Research Team, Brain, Humans, Genetic Predisposition to Disease, Risk, Cohort Studies, Attention Deficit Disorder with Hyperactivity, Gene Expression Regulation, Polymorphism, Single Nucleotide, Adolescent, Child, Child, Preschool, Female, Male, Genome-Wide Association Study, Genetic Loci, Clinical Research, Mental Health, Human Genome, Pediatric, Prevention, Genetics, Brain Disorders, Attention Deficit Hyperactivity Disorder (ADHD), Behavioral and Social Science, Aetiology, 2.1 Biological and endogenous factors, Mental health, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

Published
2019

8. Systematic single-variant and gene-based association testing of thousands of phenotypes in 394,841 UK Biobank exomes

Author

Karczewski, Konrad J., Solomonson, Matthew, Chao, Katherine R., Goodrich, Julia K., Tiao, Grace, Lu, Wenhan, Riley-Gillis, Bridget M., Tsai, Ellen A., Kim, Hye In, Zheng, Xiuwen, Rahimov, Fedik, Esmaeeli, Sahar, Grundstad, A. Jason, Reppell, Mark, Waring, Jeff, Jacob, Howard, Sexton, David, Bronson, Paola G., Chen, Xing, Hu, Xinli, Goldstein, Jacqueline I., King, Daniel, Vittal, Christopher, Poterba, Timothy, Palmer, Duncan S., Churchhouse, Claire, Howrigan, Daniel P., Zhou, Wei, Watts, Nicholas A., Nguyen, Kevin, Nguyen, Huy, Mason, Cara, Farnham, Christopher, Tolonen, Charlotte, Gauthier, Laura D., Gupta, Namrata, MacArthur, Daniel G., Rehm, Heidi L., Seed, Cotton, Philippakis, Anthony A., Daly, Mark J., Davis, J. Wade, Runz, Heiko, Miller, Melissa R., and Neale, Benjamin M.

Published
2022
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9. Deep-coverage whole genome sequences and blood lipids among 16,324 individuals.

Author

Natarajan, Pradeep, Peloso, Gina M, Zekavat, Seyedeh Maryam, Montasser, May, Ganna, Andrea, Chaffin, Mark, Khera, Amit V, Zhou, Wei, Bloom, Jonathan M, Engreitz, Jesse M, Ernst, Jason, O'Connell, Jeffrey R, Ruotsalainen, Sanni E, Alver, Maris, Manichaikul, Ani, Johnson, W Craig, Perry, James A, Poterba, Timothy, Seed, Cotton, Surakka, Ida L, Esko, Tonu, Ripatti, Samuli, Salomaa, Veikko, Correa, Adolfo, Vasan, Ramachandran S, Kellis, Manolis, Neale, Benjamin M, Lander, Eric S, Abecasis, Goncalo, Mitchell, Braxton, Rich, Stephen S, Wilson, James G, Cupples, L Adrienne, Rotter, Jerome I, Willer, Cristen J, Kathiresan, Sekar, and NHLBI TOPMed Lipids Working Group

Subjects
NHLBI TOPMed Lipids Working Group, Humans, Lipids, Base Sequence, Gene Frequency, Mutation, Genome, Human, Models, Genetic, Cholesterol, LDL, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing, Human Genome, Genetics, Digestive Diseases, Cardiovascular, Atherosclerosis, Biotechnology, 2.1 Biological and endogenous factors
Abstract

Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits-plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia.

Published
2018

10. Publisher Correction: Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

Author

Zekavat, Seyedeh M, Ruotsalainen, Sanni, Handsaker, Robert E, Alver, Maris, Bloom, Jonathan, Poterba, Timothy, Seed, Cotton, Ernst, Jason, Chaffin, Mark, Engreitz, Jesse, Peloso, Gina M, Manichaikul, Ani, Yang, Chaojie, Ryan, Kathleen A, Fu, Mao, Johnson, W Craig, Tsai, Michael, Budoff, Matthew, Vasan, Ramachandran S, Cupples, L Adrienne, Rotter, Jerome I, Rich, Stephen S, Post, Wendy, Mitchell, Braxton D, Correa, Adolfo, Metspalu, Andres, Wilson, James G, Salomaa, Veikko, Kellis, Manolis, Daly, Mark J, Neale, Benjamin M, McCarroll, Steven, Surakka, Ida, Esko, Tonu, Ganna, Andrea, Ripatti, Samuli, Kathiresan, Sekar, Natarajan, Pradeep, and NHLBI TOPMed Lipids Working Group

Subjects
NHLBI TOPMed Lipids Working Group
Abstract

The original version of this article contained an error in the name of the author Ramachandran S. Vasan, which was incorrectly given as Vasan S. Ramachandran. This has now been corrected in both the PDF and HTML versions of the article.

Published
2018

11. Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

Author

Zekavat, Seyedeh M, Ruotsalainen, Sanni, Handsaker, Robert E, Alver, Maris, Bloom, Jonathan, Poterba, Timothy, Seed, Cotton, Ernst, Jason, Chaffin, Mark, Engreitz, Jesse, Peloso, Gina M, Manichaikul, Ani, Yang, Chaojie, Ryan, Kathleen A, Fu, Mao, Johnson, W Craig, Tsai, Michael, Budoff, Matthew, Vasan, Ramachandran S, Cupples, L Adrienne, Rotter, Jerome I, Rich, Stephen S, Post, Wendy, Mitchell, Braxton D, Correa, Adolfo, Metspalu, Andres, Wilson, James G, Salomaa, Veikko, Kellis, Manolis, Daly, Mark J, Neale, Benjamin M, McCarroll, Steven, Surakka, Ida, Esko, Tonu, Ganna, Andrea, Ripatti, Samuli, Kathiresan, Sekar, Natarajan, Pradeep, and NHLBI TOPMed Lipids Working Group

Subjects
NHLBI TOPMed Lipids Working Group, Humans, Cardiovascular Diseases, Lipoprotein(a), Adaptor Proteins, Vesicular Transport, Risk Factors, Gene Expression, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome, Human, African Continental Ancestry Group, European Continental Ancestry Group, Cholesterol, LDL, Genome-Wide Association Study, DNA Copy Number Variations, Whole Genome Sequencing, Atherosclerosis, Genetics, Cardiovascular, Prevention, Human Genome, Heart Disease, 2.1 Biological and endogenous factors
Abstract

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans.

Published
2018

12. Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap

Author

Gandal, Michael J, Haney, Jillian R, Parikshak, Neelroop N, Leppa, Virpi, Ramaswami, Gokul, Hartl, Chris, Schork, Andrew J, Appadurai, Vivek, Buil, Alfonso, Werge, Thomas M, Liu, Chunyu, White, Kevin P, Horvath, Steve, Geschwind, Daniel H, Sestan, Nenad, Vaccarino, Flora, Gerstein, Mark, Weissman, Sherman, Pochareddy, Sirisha, State, Matthew, Knowles, James, Farnham, Peggy, Akbarian, Schahram, Pinto, Dalila, Van Baekl, Harm, Dracheva, Stella, Jaffe, Andrew, Hyde, Thomas, Zandi, Peter, Crawford, Gregory, Sullivan, Pat, Thompson, Wesley Kurt, Mortensen, Preben Bo, Agerbo, Esben, Pedersen, Marianne Giørtz, Pedersen, Carsten Bøcker, Mors, Ole, Børglum, Anders D, Nordentoft, Merete, Hougaard, David M, Bybjerg-Grauholm, Jonas, Bækvad-Hansen, Marie, Martin, Alicia R, Dumont, Ashley, Stevens, Christine, Churchhouse, Claire, Howrigan, Daniel P, Palmer, Duncan S, Robinson, Elise B, Satterstrom, Kyle F, Cerrato, Felecia, Huang, Hailiang, Goldstein, Jacqueline, Moran, Jennifer, Julian, Joanna Martin, Kimberly, Maller, Patrick, Chambert, Turley, Patrick, Walters, Raymond, Belliveau, Rich, Ripke, Stephan, Poterba, Timothy, Daly, Mark J, Neale, Benjamin, Fromer, Menachem, Roussos, Panos, Johnson, Jessica S, Shah, Hardik R, Mahajan, Milind C, Schadt, Eric, Haroutunian, Vahram, Ruderfer, Douglas M, Buxbaum, Joseph D, Sieberts, Solveig K, Dang, Kristen, Logsdon, Ben, Mangravite, Lara M, Peters, Mette, Gur, Raquel E, Hahn, Chang-Gyu, Devlin, Bernie, Klei, Lambertus L, Lewis, David, Lipska, Barbara, Hirai, Keisuke, Toyoshiba, Hiroyoshi, and Domenici, Enrico

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Biological Psychology, Psychology, Pharmacology and Pharmaceutical Sciences, Serious Mental Illness, Brain Disorders, Human Genome, Mental Health, Schizophrenia, Neurosciences, Bipolar Disorder, Depression, Mental Illness, 2.1 Biological and endogenous factors, Aetiology, Mental health, Good Health and Well Being, Cerebral Cortex, Gene Expression Profiling, Gene Expression Regulation, Genetic Predisposition to Disease, Humans, Mental Disorders, Multifactorial Inheritance, Nervous System Diseases, Polymorphism, Single Nucleotide, Transcription, Genetic, CommonMind Consortium, PsychENCODE Consortium, iPSYCH-BROAD Working Group, General Science & Technology
Abstract

The predisposition to neuropsychiatric disease involves a complex, polygenic, and pleiotropic genetic architecture. However, little is known about how genetic variants impart brain dysfunction or pathology. We used transcriptomic profiling as a quantitative readout of molecular brain-based phenotypes across five major psychiatric disorders-autism, schizophrenia, bipolar disorder, depression, and alcoholism-compared with matched controls. We identified patterns of shared and distinct gene-expression perturbations across these conditions. The degree of sharing of transcriptional dysregulation is related to polygenic (single-nucleotide polymorphism-based) overlap across disorders, suggesting a substantial causal genetic component. This comprehensive systems-level view of the neurobiological architecture of major neuropsychiatric illness demonstrates pathways of molecular convergence and specificity.

Published
2018

13. Pan-UK Biobank GWAS improves discovery, analysis of genetic architecture, and resolution into ancestry-enriched effects

Author

Karczewski, Konrad J, primary, Gupta, Rahul, additional, Kanai, Masahiro, additional, Lu, Wenhan, additional, Tsuo, Kristin, additional, Wang, Ying, additional, Walters, Raymond K, additional, Turley, Patrick, additional, Callier, Shawneequa, additional, Baya, Nikolas, additional, Palmer, Duncan S, additional, Goldstein, Jacqueline I, additional, Sarma, Gopal, additional, Solomonson, Matthew, additional, Cheng, Nathan, additional, Bryant, Sam, additional, Churchhouse, Claire, additional, Cusick, Caroline M, additional, Poterba, Timothy, additional, Compitello, John, additional, King, Daniel, additional, Zhou, Wei, additional, Seed, Cotton, additional, Finucane, Hilary K, additional, Daly, Mark J, additional, Neale, Benjamin M, additional, Atkinson, Elizabeth G, additional, and Martin, Alicia R, additional

Published
2024
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15. CHARR efficiently estimates contamination from DNA sequencing data

Author

Lu, Wenhan, primary, Gauthier, Laura D., additional, Poterba, Timothy, additional, Giacopuzzi, Edoardo, additional, Goodrich, Julia K., additional, Stevens, Christine R., additional, King, Daniel, additional, Daly, Mark J., additional, Neale, Benjamin M., additional, and Karczewski, Konrad J., additional

Published
2023
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16. O43: Analysis of >800,000 diverse sequenced humans in gnomAD improves clinical interpretation and provides insight into gene function

Author

Rehm, Heidi, Goodrich, Julia, Chao, Katherine, Laricchia, Kristen, Wilson, Michael, Fu, Jack, Tiao, Grace, He, Qin, Marten, Daniel, Poterba, Timothy, Vittal, Christopher, Chen, Siwei, Lu, Wenhan, Baxter, Samantha, Chapman, Sinéad, Cusick, Caroline, Darnowsky, Philip, Gauthier, Laura, Gruenschloss, Leonhard, Grant, Riley, Jahl, Stephen, Solomonson, Matthew, Stevens, Christine, MacArthur, Daniel, Talkowski, Michael, Neale, Benjamin, O'Donnell-Luria, Anne, Samocha, Kaitlin, Karczewski, Konrad, and Daly, Mark

Published
2024
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17. 17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage

Author

Marini, Sandro, Devan, William J., Radmanesh, Farid, Miyares, Laura, Poterba, Timothy, Hansen, Björn M., Norrving, Bo, Jimenez-Conde, Jordi, Giralt-Steinhauer, Eva, Elosua, Roberto, Cuadrado-Godia, Elisa, Soriano, Carolina, Roquer, Jaume, Kourkoulis, Christina E., Ayres, Alison M., Schwab, Kristin, Tirschwell, David L., Selim, Magdy, Brown, Devin L., Silliman, Scott L., Worrall, Bradford B., Meschia, James F., Kidwell, Chelsea S., Montaner, Joan, Fernandez-Cadenas, Israel, Delgado, Pilar, Greenberg, Steven M., Lindgren, Arne, Matouk, Charles, Sheth, Kevin N., Woo, Daniel, Anderson, Christopher D., Rosand, Jonathan, and Falcone, Guido J.

Published
2018
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18. Rare coding variants in 10 genes confer substantial risk for schizophrenia

Author

Singh, Tarjinder, Poterba, Timothy, Curtis, David, Akil, Huda, Al Eissa, Mariam, Barchas, Jack D., Bass, Nicholas, Bigdeli, Tim B., Breen, Gerome, Bromet, Evelyn J., Buckley, Peter F., Bunney, William E., Bybjerg-Grauholm, Jonas, Byerley, William F., Chapman, Sinéad B., Chen, Wei J., Churchhouse, Claire, Craddock, Nicholas, Cusick, Caroline M., DeLisi, Lynn, Dodge, Sheila, Escamilla, Michael A., Eskelinen, Saana, Fanous, Ayman H., Faraone, Stephen V., Fiorentino, Alessia, Francioli, Laurent, Gabriel, Stacey B., Gage, Diane, Taliun, Sarah A. Gagliano, Ganna, Andrea, Genovese, Giulio, Glahn, David C., Grove, Jakob, Hall, Mei-Hua, Hämäläinen, Eija, Heyne, Henrike O., Holi, Matti, Hougaard, David M., Howrigan, Daniel P., Huang, Hailiang, Hwu, Hai-Gwo, Kahn, René S., Kang, Hyun Min, Karczewski, Konrad J., Kirov, George, Knowles, James A., Lee, Francis S., Lehrer, Douglas S., Lescai, Francesco, Malaspina, Dolores, Marder, Stephen R., McCarroll, Steven A., McIntosh, Andrew M., Medeiros, Helena, Milani, Lili, Morley, Christopher P., Morris, Derek W., Bo Mortensen, Preben, Myers, Richard M., Nordentoft, Merete, O’Brien, Niamh L., Olivares, Ana Maria, Ongur, Dost, Ouwehand, Willem H., Palmer, Duncan S., Paunio, Tiina, Quested, Digby, Rapaport, Mark H., Rees, Elliott, Rollins, Brandi, Satterstrom, F. Kyle, Schatzberg, Alan, Scolnick, Edward, Scott, Laura J., Sharp, Sally I., Sklar, Pamela, Smoller, Jordan W., Sobell, Janet l., Solomonson, Matthew, Stevens, Christine R., Suvisaari, Jaana, Tiao, Grace, Watson, Stanley J., Watts, Nicholas A., Blackwood, Douglas H., Børglum, Anders D., Cohen, Bruce M., Corvin, Aiden P., Esko, Tõnu, Freimer, Nelson B., Glatt, Stephen J., Hultman, Christina M., McQuillin, Andrew, Palotie, Aarno, Pato, Carlos N., Pato, Michele T., Pulver, Ann E., St. Clair, David, Tsuang, Ming T., Vawter, Marquis P., Walters, James T., Werge, Thomas M., Ophoff, Roel A., Sullivan, Patrick F., Owen, Michael J., Boehnke, Michael, O’Donovan, Michael C., Neale, Benjamin M., and Daly, Mark J.

Subjects
Article
Abstract

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analyzing the whole-exomes of 24,248 cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in ten genes as conferring substantial risk for schizophrenia (odds ratios 3 – 50, P < 2.14 × 10(−6)), and 32 genes at a FDR < 5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure, and function of the synapse. The associations of NMDA receptor subunit GRIN2A and AMPA receptor subunit GRIA3 provide support for the dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk between schizophrenia, autism spectrum disorders (ASD)(1), epilepsy and severe neurodevelopmental disorders (DD/ID)(2), though in some shared genes different mutation types are implicated. Most genes described here however are not implicated in neurodevelopment and we demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk(3), suggesting that common and rare genetic risk factors at least partially converge on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, implying that more risk genes await discovery using this approach.

Published
2022

19. Bayesian model comparison for rare-variant association studies

Author

Venkataraman, Guhan Ram, primary, DeBoever, Christopher, additional, Tanigawa, Yosuke, additional, Aguirre, Matthew, additional, Ioannidis, Alexander G., additional, Mostafavi, Hakhamanesh, additional, Spencer, Chris C.A., additional, Poterba, Timothy, additional, Bustamante, Carlos D., additional, Daly, Mark J., additional, Pirinen, Matti, additional, and Rivas, Manuel A., additional

Published
2021
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20. Systematic single-variant and gene-based association testing of thousands of phenotypes in 426,370 UK Biobank exomes

Author

Karczewski, Konrad J., primary, Solomonson, Matthew, additional, Chao, Katherine R., additional, Goodrich, Julia K., additional, Tiao, Grace, additional, Lu, Wenhan, additional, Riley-Gillis, Bridget M., additional, Tsai, Ellen A., additional, Kim, Hye In, additional, Zheng, Xiuwen, additional, Rahimov, Fedik, additional, Esmaeeli, Sahar, additional, Grundstad, A. Jason, additional, Reppell, Mark, additional, Waring, Jeff, additional, Jacob, Howard, additional, Sexton, David, additional, Bronson, Paola G., additional, Chen, Xing, additional, Hu, Xinli, additional, Goldstein, Jacqueline I., additional, King, Daniel, additional, Vittal, Christopher, additional, Poterba, Timothy, additional, Palmer, Duncan S., additional, Churchhouse, Claire, additional, Howrigan, Daniel P., additional, Zhou, Wei, additional, Watts, Nicholas A., additional, Nguyen, Kevin, additional, Nguyen, Huy, additional, Mason, Cara, additional, Farnham, Christopher, additional, Tolonen, Charlotte, additional, Gauthier, Laura D., additional, Gupta, Namrata, additional, MacArthur, Daniel G., additional, Rehm, Heidi L., additional, Seed, Cotton, additional, Philippakis, Anthony A., additional, Daly, Mark J., additional, Davis, J. Wade, additional, Runz, Heiko, additional, Miller, Melissa R., additional, and Neale, Benjamin M., additional

Published
2021
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21. Author Correction: The mutational constraint spectrum quantified from variation in 141,456 humanS

Author

Karczewski, Konrad J., Francioli, Laurent C., Tiao, Grace, Cummings, Beryl B., Alföldi, Jessica, Wang, Qingbo, Collins, Ryan L., Laricchia, Kristen M., Ganna, Andrea, Birnbaum, Daniel P., Gauthier, Laura D., Brand, Harrison, Solomonson, Matthew, Rhodes, Daniel, Singer-Berk, Moriel, England, Eleina M., Seaby, Eleanor G., Kosmicki, Jack A., Walters, Raymond K., Tashman, Katherine, Farjoun, Yossi, Banks, Eric, Poterba, Timothy, Wang, Arcturus, Seed, Cotton, Whiffin, Nicola, Chong, Jessica X., Samocha, Kaitlin E., Pierce-Hoffman, Emma, Zappala, Zachary, O’Donnell-Luria, Anne H., Minikel, Eric Vallabh, Weisburd, Ben, Lek, Monkol, Ware, James S., Vittal, Christopher, Armean, Irina M., Bergelson, Louis, Cibulskis, Kristian, Connolly, Kristen M., Covarrubias, Miguel, Donnelly, Stacey, Ferriera, Steven, Gabriel, Stacey, Gentry, Jeff, Gupta, Namrata, Jeandet, Thibault, Kaplan, Diane, Llanwarne, Christopher, Munshi, Ruchi, Novod, Sam, Petrillo, Nikelle, Roazen, David, Ruano-Rubio, Valentin, Saltzman, Andrea, Schleicher, Molly, Soto, Jose, Tibbetts, Kathleen, Tolonen, Charlotte, Wade, Gordon, Talkowski, Michael E., Aguilar Salinas, Carlos A., Ahmad, Tariq, Albert, Christine M., Ardissino, Diego, Atzmon, Gil, Barnard, John, Beaugerie, Laurent, Benjamin, Emelia J., Boehnke, Michael, Bonnycastle, Lori L., Bottinger, Erwin P., Bowden, Donald W., Bown, Matthew J., Chambers, John C., Chan, Juliana C., Chasman, Daniel, Cho, Judy, Chung, Mina K., Cohen, Bruce, Correa, Adolfo, Dabelea, Dana, Daly, Mark J., Darbar, Dawood, Duggirala, Ravindranath, Dupuis, Josée, Ellinor, Patrick T., Elosua, Roberto, Erdmann, Jeanette, Esko, Tõnu, Färkkilä, Martti, Florez, Jose, Franke, Andre, Getz, Gad, Glaser, Benjamin, Glatt, Stephen J., Goldstein, David, Gonzalez, Clicerio, Groop, Leif, Haiman, Christopher, Hanis, Craig, Harms, Matthew, Hiltunen, Mikko, Holi, Matti M., Hultman, Christina M., Kallela, Mikko, Kaprio, Jaakko, Kathiresan, Sekar, Kim, Bong Jo, Kim, Young Jin, Kirov, George, Kooner, Jaspal, Koskinen, Seppo, Krumholz, Harlan M., Kugathasan, Subra, Kwak, Soo Heon, Laakso, Markku, Lehtimäki, Terho, Loos, Ruth J.F., Lubitz, Steven A., Ma, Ronald C.W., MacArthur, Daniel G., Marrugat, Jaume, Mattila, Kari M., McCarthy, Mark I., McGovern, Dermot, McPherson, Ruth, Meigs, James B., Melander, Olle, Metspalu, Andres, Neale, Benjamin M., Nilsson, Peter M., O’Donovan, Michael C., Ongur, Dost, Orozco, Lorena, Palotie, Aarno, Park, Kyong Soo, Pato, Carlos, Pulver, Ann E., Rahman, Nazneen, Remes, Anne M., Rioux, John D., Ripatti, Samuli, Roden, Dan M., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Scharf, Jeremiah, Schunkert, Heribert, Shoemaker, Moore B., Sklar, Pamela, Soininen, Hilkka, Sokol, Harry, Spector, Tim, Sullivan, Patrick F., Suvisaari, Jaana, Tai, E. Shyong, Teo, Yik Ying, Tiinamaija, Tuomi, Tsuang, Ming, Turner, Dan, Tusie-Luna, Teresa, Vartiainen, Erkki, Vawter, Marquis P., Watkins, Hugh, Weersma, Rinse K., Wessman, Maija, and Xavier, Ramnik J.

Subjects
Multidisciplinary, Science & Technology, General Science & Technology, Spectrum (functional analysis), Rare variants, Biology, Constraint (information theory), Multidisciplinary Sciences, Variation (linguistics), Genome Aggregation Database Consortium, Science & Technology - Other Topics, Author Correction, Medical genomics, Algorithm
Abstract

In this Article, author Marquis P. Vawter was missing from the Genome Aggregation Database Consortium list. They are associated with the affiliation: ‘Department of Psychiatry & Human Behavior, University of California Irvine, Irvine, CA, USA’, and contributed to the generation of the primary data incorporated into the gnomAD resource. In addition, in the legend to Fig. 1, ‘ten’ should have been ‘seven’ in the sentence: “a, Uniform manifold approximation and projection (UMAP)46,47 plot depicting the ancestral diversity of all individuals in gnomAD, using seven principal components.” The original Article has been corrected online.

Published
2021

22. Evaluating drug targets through human loss-of-function genetic variation

Author

Minikel, Eric Vallabh, Karczewski, Konrad J., Martin, Hilary C., Cummings, Beryl B., Whiffin, Nicola, Rhodes, Daniel, Alföldi, Jessica, Trembath, Richard C., van Heel, David A., Daly, Mark J., Armean, Irina M., Banks, Eric, Bergelson, Louis, Cibulskis, Kristian, Collins, Ryan L., Connolly, Kristen M., Covarrubias, Miguel, Donnelly, Stacey, Farjoun, Yossi, Ferriera, Steven, Francioli, Laurent, Gabriel, Stacey, Gauthier, Laura D., Gentry, Jeff, Gupta, Namrata, Jeandet, Thibault, Kaplan, Diane, Laricchia, Kristen M., Llanwarne, Christopher, Minikel, Eric V., Munshi, Ruchi, Neale, Benjamin M., Novod, Sam, O’Donnell-Luria, Anne H., Petrillo, Nikelle, Poterba, Timothy, Roazen, David, Ruano-Rubio, Valentin, Saltzman, Andrea, Samocha, Kaitlin E., Schleicher, Molly, Seed, Cotton, Solomonson, Matthew, Soto, Jose, Tiao, Grace, Tibbetts, Kathleen, Centre of Excellence in Complex Disease Genetics, Department of Medicine, Clinicum, Gastroenterologian yksikkö, HUS Abdominal Center, HUS Psychiatry, Department of Psychiatry, HUS Neurocenter, Department of Neurosciences, Institute for Molecular Medicine Finland, Department of Public Health, Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, University Management, Biostatistics Helsinki, Biosciences, Genomics of Neurological and Neuropsychiatric Disorders, Aarno Palotie / Principal Investigator, Tampere University, Clinical Medicine, and Department of Clinical Chemistry

Subjects
Drug, FAMILIAL PRION DISEASE, PENETRANCE, media_common.quotation_subject, ved/biology.organism_classification_rank.species, PROTEIN, Computational biology, Biology, VARIANTS, Compound heterozygosity, AMYOTROPHIC-LATERAL-SCLEROSIS, Target validation, 03 medical and health sciences, 0302 clinical medicine, PARKINSONS-DISEASE, In vivo, Genetic variation, EPIDEMIOLOGY, Model organism, Gene, Loss function, 030304 developmental biology, media_common, 0303 health sciences, Multidisciplinary, ved/biology, MUTATIONS, 1184 Genetics, developmental biology, physiology, HUNTINGTONS-DISEASE GENE, Genomics, 3. Good health, PREVALENCE, Drug development, 3111 Biomedicine, 030217 neurology & neurosurgery, Analysis
Abstract

Naturally occurring human genetic variants that are predicted to inactivate protein-coding genes provide an in vivo model of human gene inactivation that complements knockout studies in cells and model organisms. Here we report three key findings regarding the assessment of candidate drug targets using human loss-of-function variants. First, even essential genes, in which loss-of-function variants are not tolerated, can be highly successful as targets of inhibitory drugs. Second, in most genes, loss-of-function variants are sufficiently rare that genotype-based ascertainment of homozygous or compound heterozygous ‘knockout’ humans will await sample sizes that are approximately 1,000 times those presently available, unless recruitment focuses on consanguineous individuals. Third, automated variant annotation and filtering are powerful, but manual curation remains crucial for removing artefacts, and is a prerequisite for recall-by-genotype efforts. Our results provide a roadmap for human knockout studies and should guide the interpretation of loss-of-function variants in drug development., Analysis of predicted loss-of-function variants from 125,748 human exomes and 15,708 whole genomes in the Genome Aggregation Database (gnomAD) provides a roadmap for human ‘knockout’ studies and a guide for future research into disease biology and drug-target selection.

Published
2020

23. Transcript expression-aware annotation improves rare variant interpretation

Author

Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, Cummings, Beryl B., Karczewski, Konrad J., Kosmicki, Jack A., Seaby, Eleanor G., Watts, Nicholas A., Singer-Berk, Moriel, Mudge, Jonathan M., Karjalainen, Juha, Satterstrom, F. Kyle, O’Donnell-Luria, Anne H., Poterba, Timothy, Seed, Cotton, Solomonson, Matthew, Alföldi, Jessica, Armean, Irina M., Banks, Eric, Bergelson, Louis, Cibulskis, Kristian, Collins, Ryan L., Connolly, Kristen M., Covarrubias, Miguel, Daly, Mark J., Donnelly, Stacey, Farjoun, Yossi, Ferriera, Steven, Francioli, Laurent, Gabriel, Stacey, Gauthier, Laura D., Gentry, Jeff, Gupta, Namrata, Jeandet, Thibault, Kaplan, Diane, Laricchia, Kristen M., Llanwarne, Christopher, Minikel, Eric V., Munshi, Ruchi, Neale, Benjamin M., Novod, Sam, Petrillo, Nikelle, Roazen, David, Ruano-Rubio, Valentin, Saltzman, Andrea, Lehtimäki, Terho, Mattila, Kari M., Suvisaari, Jaana, Tampere University, Clinical Medicine, Department of Clinical Chemistry, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Department of Medicine, Clinicum, Gastroenterologian yksikkö, HUS Psychiatry, Department of Psychiatry, HUS Neurocenter, Department of Neurosciences, Neurologian yksikkö, Institute for Molecular Medicine Finland, Department of Public Health, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, Biosciences, Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, and Biostatistics Helsinki

Subjects
Male, Transcription, Genetic, Autism Spectrum Disorder, Developmental Disabilities, Datasets as Topic, Haploinsufficiency, Human genetic variation, Genome, Exon, 0302 clinical medicine, Loss of Function Mutation, Disease, Poisson Distribution, Exome sequencing, 0303 health sciences, education.field_of_study, Multidisciplinary, Disease genetics, ARRHYTHMIA, 1184 Genetics, developmental biology, physiology, Genome Aggregation Database Production Team, Exons, Female, Medical genomics, GENES, Genotype, General Science & Technology, Population, Computational biology, Biology, 3121 Internal medicine, Article, DNA sequencing, 03 medical and health sciences, Rare Diseases, Intellectual Disability, Exome Sequencing, Humans, RNA, Messenger, Author Correction, Transcriptomics, education, Gene, 030304 developmental biology, MUTATIONS, Alternative splicing, Reproducibility of Results, Molecular Sequence Annotation, Genome Aggregation Database Consortium, 3111 Biomedicine, Transcriptome, 030217 neurology & neurosurgery
Abstract

The acceleration of DNA sequencing in samples from patients and population studies has resulted in extensive catalogues of human genetic variation, but the interpretation of rare genetic variants remains problematic. A notable example of this challenge is the existence of disruptive variants in dosage-sensitive disease genes, even in apparently healthy individuals. Here, by manual curation of putative loss-of-function (pLoF) variants in haploinsufficient disease genes in the Genome Aggregation Database (gnomAD)1, we show that one explanation for this paradox involves alternative splicing of mRNA, which allows exons of a gene to be expressed at varying levels across different cell types. Currently, no existing annotation tool systematically incorporates information about exon expression into the interpretation of variants. We develop a transcript-level annotation metric known as the ‘proportion expressed across transcripts’, which quantifies isoform expression for variants. We calculate this metric using 11,706 tissue samples from the Genotype Tissue Expression (GTEx) project2 and show that it can differentiate between weakly and highly evolutionarily conserved exons, a proxy for functional importance. We demonstrate that expression-based annotation selectively filters 22.8% of falsely annotated pLoF variants found in haploinsufficient disease genes in gnomAD, while removing less than 4% of high-confidence pathogenic variants in the same genes. Finally, we apply our expression filter to the analysis of de novo variants in patients with autism spectrum disorder and intellectual disability or developmental disorders to show that pLoF variants in weakly expressed regions have similar effect sizes to those of synonymous variants, whereas pLoF variants in highly expressed exons are most strongly enriched among cases. Our annotation is fast, flexible and generalizable, making it possible for any variant file to be annotated with any isoform expression dataset, and will be valuable for the genetic diagnosis of rare diseases, the analysis of rare variant burden in complex disorders, and the curation and prioritization of variants in recall-by-genotype studies., A novel variant annotation metric that quantifies the level of expression of genetic variants across tissues is validated in the Genome Aggregation Database (gnomAD) and is shown to improve rare variant interpretation.

Published
2020

24. Deep-coverage whole genome sequences and blood lipids among 16,324 individuals

Author

Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Natarajan, Pradeep, Peloso, Gina M., Zekavat, Seyedeh Maryam, Montasser, May, Ganna, Andrea, Chaffin, Mark, Khera, Amit V., Zhou, Wei, Bloom, Jonathan M., Engreitz, Jesse M., Ernst, Jason, O’Connell, Jeffrey R., Ruotsalainen, Sanni E., Alver, Maris, Manichaikul, Ani, Johnson, W. Craig, Perry, James A., Poterba, Timothy, Seed, Cotton, Surakka, Ida L., Esko, Tonu, Ripatti, Samuli, Salomaa, Veikko, Correa, Adolfo, Vasan, Ramachandran S., Kellis, Manolis, Neale, Benjamin M., Lander, Eric S., Abecasis, Goncalo, Mitchell, Braxton, Rich, Stephen S., Wilson, James G., Cupples, L. Adrienne, Rotter, Jerome I., Willer, Cristen J., Kathiresan, Sekar, Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Natarajan, Pradeep, Peloso, Gina M., Zekavat, Seyedeh Maryam, Montasser, May, Ganna, Andrea, Chaffin, Mark, Khera, Amit V., Zhou, Wei, Bloom, Jonathan M., Engreitz, Jesse M., Ernst, Jason, O’Connell, Jeffrey R., Ruotsalainen, Sanni E., Alver, Maris, Manichaikul, Ani, Johnson, W. Craig, Perry, James A., Poterba, Timothy, Seed, Cotton, Surakka, Ida L., Esko, Tonu, Ripatti, Samuli, Salomaa, Veikko, Correa, Adolfo, Vasan, Ramachandran S., Kellis, Manolis, Neale, Benjamin M., Lander, Eric S., Abecasis, Goncalo, Mitchell, Braxton, Rich, Stephen S., Wilson, James G., Cupples, L. Adrienne, Rotter, Jerome I., Willer, Cristen J., and Kathiresan, Sekar

Abstract

Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits—plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia.

Published
2020

25. Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism

Author

Satterstrom, F. Kyle, primary, Kosmicki, Jack A., additional, Wang, Jiebiao, additional, Breen, Michael S., additional, De Rubeis, Silvia, additional, An, Joon-Yong, additional, Peng, Minshi, additional, Collins, Ryan, additional, Grove, Jakob, additional, Klei, Lambertus, additional, Stevens, Christine, additional, Reichert, Jennifer, additional, Mulhern, Maureen S., additional, Artomov, Mykyta, additional, Gerges, Sherif, additional, Sheppard, Brooke, additional, Xu, Xinyi, additional, Bhaduri, Aparna, additional, Norman, Utku, additional, Brand, Harrison, additional, Schwartz, Grace, additional, Nguyen, Rachel, additional, Guerrero, Elizabeth E., additional, Dias, Caroline, additional, Betancur, Catalina, additional, Cook, Edwin H., additional, Gallagher, Louise, additional, Gill, Michael, additional, Sutcliffe, James S., additional, Thurm, Audrey, additional, Zwick, Michael E., additional, Børglum, Anders D., additional, State, Matthew W., additional, Cicek, A. Ercument, additional, Talkowski, Michael E., additional, Cutler, David J., additional, Devlin, Bernie, additional, Sanders, Stephan J., additional, Roeder, Kathryn, additional, Daly, Mark J., additional, Buxbaum, Joseph D., additional, Aleksic, Branko, additional, Anney, Richard, additional, Barbosa, Mafalda, additional, Bishop, Somer, additional, Brusco, Alfredo, additional, Bybjerg-Grauholm, Jonas, additional, Carracedo, Angel, additional, Chan, Marcus C.Y., additional, Chiocchetti, Andreas G., additional, Chung, Brian H.Y., additional, Coon, Hilary, additional, Cuccaro, Michael L., additional, Curró, Aurora, additional, Dalla Bernardina, Bernardo, additional, Doan, Ryan, additional, Domenici, Enrico, additional, Dong, Shan, additional, Fallerini, Chiara, additional, Fernández-Prieto, Montserrat, additional, Ferrero, Giovanni Battista, additional, Freitag, Christine M., additional, Fromer, Menachem, additional, Gargus, J. Jay, additional, Geschwind, Daniel, additional, Giorgio, Elisa, additional, González-Peñas, Javier, additional, Guter, Stephen, additional, Halpern, Danielle, additional, Hansen-Kiss, Emily, additional, He, Xin, additional, Herman, Gail E., additional, Hertz-Picciotto, Irva, additional, Hougaard, David M., additional, Hultman, Christina M., additional, Ionita-Laza, Iuliana, additional, Jacob, Suma, additional, Jamison, Jesslyn, additional, Jugessur, Astanand, additional, Kaartinen, Miia, additional, Knudsen, Gun Peggy, additional, Kolevzon, Alexander, additional, Kushima, Itaru, additional, Lee, So Lun, additional, Lehtimäki, Terho, additional, Lim, Elaine T., additional, Lintas, Carla, additional, Lipkin, W. Ian, additional, Lopergolo, Diego, additional, Lopes, Fátima, additional, Ludena, Yunin, additional, Maciel, Patricia, additional, Magnus, Per, additional, Mahjani, Behrang, additional, Maltman, Nell, additional, Manoach, Dara S., additional, Meiri, Gal, additional, Menashe, Idan, additional, Miller, Judith, additional, Minshew, Nancy, additional, Montenegro, Eduarda M.S., additional, Moreira, Danielle, additional, Morrow, Eric M., additional, Mors, Ole, additional, Mortensen, Preben Bo, additional, Mosconi, Matthew, additional, Muglia, Pierandrea, additional, Neale, Benjamin M., additional, Nordentoft, Merete, additional, Ozaki, Norio, additional, Palotie, Aarno, additional, Parellada, Mara, additional, Passos-Bueno, Maria Rita, additional, Pericak-Vance, Margaret, additional, Persico, Antonio M., additional, Pessah, Isaac, additional, Puura, Kaija, additional, Reichenberg, Abraham, additional, Renieri, Alessandra, additional, Riberi, Evelise, additional, Robinson, Elise B., additional, Samocha, Kaitlin E., additional, Sandin, Sven, additional, Santangelo, Susan L., additional, Schellenberg, Gerry, additional, Scherer, Stephen W., additional, Schlitt, Sabine, additional, Schmidt, Rebecca, additional, Schmitt, Lauren, additional, Silva, Isabela M.W., additional, Singh, Tarjinder, additional, Siper, Paige M., additional, Smith, Moyra, additional, Soares, Gabriela, additional, Stoltenberg, Camilla, additional, Suren, Pål, additional, Susser, Ezra, additional, Sweeney, John, additional, Szatmari, Peter, additional, Tang, Lara, additional, Tassone, Flora, additional, Teufel, Karoline, additional, Trabetti, Elisabetta, additional, Trelles, Maria del Pilar, additional, Walsh, Christopher A., additional, Weiss, Lauren A., additional, Werge, Thomas, additional, Werling, Donna M., additional, Wigdor, Emilie M., additional, Wilkinson, Emma, additional, Willsey, A. Jeremy, additional, Yu, Timothy W., additional, Yu, Mullin H.C., additional, Yuen, Ryan, additional, Zachi, Elaine, additional, Agerbo, Esben, additional, Als, Thomas Damm, additional, Appadurai, Vivek, additional, Bækvad-Hansen, Marie, additional, Belliveau, Rich, additional, Buil, Alfonso, additional, Carey, Caitlin E., additional, Cerrato, Felecia, additional, Chambert, Kimberly, additional, Churchhouse, Claire, additional, Dalsgaard, Søren, additional, Demontis, Ditte, additional, Dumont, Ashley, additional, Goldstein, Jacqueline, additional, Hansen, Christine S., additional, Hauberg, Mads Engel, additional, Hollegaard, Mads V., additional, Howrigan, Daniel P., additional, Huang, Hailiang, additional, Maller, Julian, additional, Martin, Alicia R., additional, Martin, Joanna, additional, Mattheisen, Manuel, additional, Moran, Jennifer, additional, Pallesen, Jonatan, additional, Palmer, Duncan S., additional, Pedersen, Carsten Bøcker, additional, Pedersen, Marianne Giørtz, additional, Poterba, Timothy, additional, Poulsen, Jesper Buchhave, additional, Ripke, Stephan, additional, Schork, Andrew J., additional, Thompson, Wesley K., additional, Turley, Patrick, additional, and Walters, Raymond K., additional

Published
2020
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26. Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Author

Lee, Phil H., primary, Anttila, Verneri, additional, Won, Hyejung, additional, Feng, Yen-Chen A., additional, Rosenthal, Jacob, additional, Zhu, Zhaozhong, additional, Tucker-Drob, Elliot M., additional, Nivard, Michel G., additional, Grotzinger, Andrew D., additional, Posthuma, Danielle, additional, Wang, Meg M.-J., additional, Yu, Dongmei, additional, Stahl, Eli A., additional, Walters, Raymond K., additional, Anney, Richard J.L., additional, Duncan, Laramie E., additional, Ge, Tian, additional, Adolfsson, Rolf, additional, Banaschewski, Tobias, additional, Belangero, Sintia, additional, Cook, Edwin H., additional, Coppola, Giovanni, additional, Derks, Eske M., additional, Hoekstra, Pieter J., additional, Kaprio, Jaakko, additional, Keski-Rahkonen, Anna, additional, Kirov, George, additional, Kranzler, Henry R., additional, Luykx, Jurjen J., additional, Rohde, Luis A., additional, Zai, Clement C., additional, Agerbo, Esben, additional, Arranz, M.J., additional, Asherson, Philip, additional, Bækvad-Hansen, Marie, additional, Baldursson, Gísli, additional, Bellgrove, Mark, additional, Belliveau, Richard A., additional, Buitelaar, Jan, additional, Burton, Christie L., additional, Bybjerg-Grauholm, Jonas, additional, Casas, Miquel, additional, Cerrato, Felecia, additional, Chambert, Kimberly, additional, Churchhouse, Claire, additional, Cormand, Bru, additional, Crosbie, Jennifer, additional, Dalsgaard, Søren, additional, Demontis, Ditte, additional, Doyle, Alysa E., additional, Dumont, Ashley, additional, Elia, Josephine, additional, Grove, Jakob, additional, Gudmundsson, Olafur O., additional, Haavik, Jan, additional, Hakonarson, Hakon, additional, Hansen, Christine S., additional, Hartman, Catharina A., additional, Hawi, Ziarih, additional, Hervás, Amaia, additional, Hougaard, David M., additional, Howrigan, Daniel P., additional, Huang, Hailiang, additional, Kuntsi, Jonna, additional, Langley, Kate, additional, Lesch, Klaus-Peter, additional, Leung, Patrick W.L., additional, Loo, Sandra K., additional, Martin, Joanna, additional, Martin, Alicia R., additional, McGough, James J., additional, Medland, Sarah E., additional, Moran, Jennifer L., additional, Mors, Ole, additional, Mortensen, Preben B., additional, Oades, Robert D., additional, Palmer, Duncan S., additional, Pedersen, Carsten B., additional, Pedersen, Marianne G., additional, Peters, Triinu, additional, Poterba, Timothy, additional, Poulsen, Jesper B., additional, Ramos-Quiroga, Josep Antoni, additional, Reif, Andreas, additional, Ribasés, Marta, additional, Rothenberger, Aribert, additional, Rovira, Paula, additional, Sánchez-Mora, Cristina, additional, Satterstrom, F. Kyle, additional, Schachar, Russell, additional, Artigas, Maria Soler, additional, Steinberg, Stacy, additional, Stefansson, Hreinn, additional, Turley, Patrick, additional, Walters, G. Bragi, additional, Werge, Thomas, additional, Zayats, Tetyana, additional, Arking, Dan E., additional, Bettella, Francesco, additional, Buxbaum, Joseph D., additional, Christensen, Jane H., additional, Collins, Ryan L., additional, Coon, Hilary, additional, De Rubeis, Silvia, additional, Delorme, Richard, additional, Grice, Dorothy E., additional, Hansen, Thomas F., additional, Holmans, Peter A., additional, Hope, Sigrun, additional, Hultman, Christina M., additional, Klei, Lambertus, additional, Ladd-Acosta, Christine, additional, Magnusson, Pall, additional, Nærland, Terje, additional, Nyegaard, Mette, additional, Pinto, Dalila, additional, Qvist, Per, additional, Rehnström, Karola, additional, Reichenberg, Abraham, additional, Reichert, Jennifer, additional, Roeder, Kathryn, additional, Rouleau, Guy A., additional, Saemundsen, Evald, additional, Sanders, Stephan J., additional, Sandin, Sven, additional, St Pourcain, Beate, additional, Stefansson, Kari, additional, Sutcliffe, James S., additional, Talkowski, Michael E., additional, Weiss, Lauren A., additional, Willsey, A. Jeremy, additional, Agartz, Ingrid, additional, Akil, Huda, additional, Albani, Diego, additional, Alda, Martin, additional, Als, Thomas D., additional, Anjorin, Adebayo, additional, Backlund, Lena, additional, Bass, Nicholas, additional, Bauer, Michael, additional, Baune, Bernhard T., additional, Bellivier, Frank, additional, Bergen, Sarah E., additional, Berrettini, Wade H., additional, Biernacka, Joanna M., additional, Blackwood, Douglas H.R., additional, Bøen, Erlend, additional, Budde, Monika, additional, Bunney, William, additional, Burmeister, Margit, additional, Byerley, William, additional, Byrne, Enda M., additional, Cichon, Sven, additional, Clarke, Toni-Kim, additional, Coleman, Jonathan R.I., additional, Craddock, Nicholas, additional, Curtis, David, additional, Czerski, Piotr M., additional, Dale, Anders M., additional, Dalkner, Nina, additional, Dannlowski, Udo, additional, Degenhardt, Franziska, additional, Di Florio, Arianna, additional, Elvsåshagen, Torbjørn, additional, Etain, Bruno, additional, Fischer, Sascha B., additional, Forstner, Andreas J., additional, Forty, Liz, additional, Frank, Josef, additional, Frye, Mark, additional, Fullerton, Janice M., additional, Gade, Katrin, additional, Gaspar, Héléna A., additional, Gershon, Elliot S., additional, Gill, Michael, additional, Goes, Fernando S., additional, Gordon, Scott D., additional, Gordon-Smith, Katherine, additional, Green, Melissa J., additional, Greenwood, Tiffany A., additional, Grigoroiu-Serbanescu, Maria, additional, Guzman-Parra, José, additional, Hauser, Joanna, additional, Hautzinger, Martin, additional, Heilbronner, Urs, additional, Herms, Stefan, additional, Hoffmann, Per, additional, Holland, Dominic, additional, Jamain, Stéphane, additional, Jones, Ian, additional, Jones, Lisa A., additional, Kandaswamy, Radhika, additional, Kelsoe, John R., additional, Kennedy, James L., additional, Joachim, Oedegaard Ketil, additional, Kittel-Schneider, Sarah, additional, Kogevinas, Manolis, additional, Koller, Anna C., additional, Lavebratt, Catharina, additional, Lewis, Cathryn M., additional, Li, Qingqin S., additional, Lissowska, Jolanta, additional, Loohuis, Loes M.O., additional, Lucae, Susanne, additional, Maaser, Anna, additional, Malt, Ulrik F., additional, Martin, Nicholas G., additional, Martinsson, Lina, additional, McElroy, Susan L., additional, McMahon, Francis J., additional, McQuillin, Andrew, additional, Melle, Ingrid, additional, Metspalu, Andres, additional, Millischer, Vincent, additional, Mitchell, Philip B., additional, Montgomery, Grant W., additional, Morken, Gunnar, additional, Morris, Derek W., additional, Müller-Myhsok, Bertram, additional, Mullins, Niamh, additional, Myers, Richard M., additional, Nievergelt, Caroline M., additional, Nordentoft, Merete, additional, Adolfsson, Annelie Nordin, additional, Nöthen, Markus M., additional, Ophoff, Roel A., additional, Owen, Michael J., additional, Paciga, Sara A., additional, Pato, Carlos N., additional, Pato, Michele T., additional, Perlis, Roy H., additional, Perry, Amy, additional, Potash, James B., additional, Reinbold, Céline S., additional, Rietschel, Marcella, additional, Rivera, Margarita, additional, Roberson, Mary, additional, Schalling, Martin, additional, Schofield, Peter R., additional, Schulze, Thomas G., additional, Scott, Laura J., additional, Serretti, Alessandro, additional, Sigurdsson, Engilbert, additional, Smeland, Olav B., additional, Stordal, Eystein, additional, Streit, Fabian, additional, Strohmaier, Jana, additional, Thorgeirsson, Thorgeir E., additional, Treutlein, Jens, additional, Turecki, Gustavo, additional, Vaaler, Arne E., additional, Vieta, Eduard, additional, Vincent, John B., additional, Wang, Yunpeng, additional, Witt, Stephanie H., additional, Zandi, Peter, additional, Adan, Roger A.H., additional, Alfredsson, Lars, additional, Ando, Tetsuya, additional, Aschauer, Harald, additional, Baker, Jessica H., additional, Bencko, Vladimir, additional, Bergen, Andrew W., additional, Birgegård, Andreas, additional, Perica, Vesna Boraska, additional, Brandt, Harry, additional, Burghardt, Roland, additional, Carlberg, Laura, additional, Cassina, Matteo, additional, Clementi, Maurizio, additional, Courtet, Philippe, additional, Crawford, Steven, additional, Crow, Scott, additional, Crowley, James J., additional, Danner, Unna N., additional, Davis, Oliver S.P., additional, Degortes, Daniela, additional, DeSocio, Janiece E., additional, Dick, Danielle M., additional, Dina, Christian, additional, Docampo, Elisa, additional, Egberts, Karin, additional, Ehrlich, Stefan, additional, Espeseth, Thomas, additional, Fernández-Aranda, Fernando, additional, Fichter, Manfred M., additional, Foretova, Lenka, additional, Forzan, Monica, additional, Gambaro, Giovanni, additional, Giegling, Ina, additional, Gonidakis, Fragiskos, additional, Gorwood, Philip, additional, Mayora, Monica Gratacos, additional, Guo, Yiran, additional, Halmi, Katherine A., additional, Hatzikotoulas, Konstantinos, additional, Hebebrand, Johannes, additional, Helder, Sietske G., additional, Herpertz-Dahlmann, Beate, additional, Herzog, Wolfgang, additional, Hinney, Anke, additional, Imgart, Hartmut, additional, Jiménez-Murcia, Susana, additional, Johnson, Craig, additional, Jordan, Jennifer, additional, Julià, Antonio, additional, Kaminská, Deborah, additional, Karhunen, Leila, additional, Karwautz, Andreas, additional, Kas, Martien J.H., additional, Kaye, Walter H., additional, Kennedy, Martin A., additional, Kim, Youl-Ri, additional, Klareskog, Lars, additional, Klump, Kelly L., additional, Knudsen, Gun Peggy S., additional, Landén, Mikael, additional, Le Hellard, Stephanie, additional, Levitan, Robert D., additional, Li, Dong, additional, Lichtenstein, Paul, additional, Maj, Mario, additional, Marsal, Sara, additional, McDevitt, Sara, additional, Mitchell, James, additional, Monteleone, Palmiero, additional, Monteleone, Alessio Maria, additional, Munn-Chernoff, Melissa A., additional, Nacmias, Benedetta, additional, Navratilova, Marie, additional, O’Toole, Julie K., additional, Padyukov, Leonid, additional, Pantel, Jacques, additional, Papezova, Hana, additional, Rabionet, Raquel, additional, Raevuori, Anu, additional, Ramoz, Nicolas, additional, Reichborn-Kjennerud, Ted, additional, Ricca, Valdo, additional, Roberts, Marion, additional, Rujescu, Dan, additional, Rybakowski, Filip, additional, Scherag, André, additional, Schmidt, Ulrike, additional, Seitz, Jochen, additional, Slachtova, Lenka, additional, Slof-Op‘t Landt, Margarita C.T., additional, Slopien, Agnieszka, additional, Sorbi, Sandro, additional, Southam, Lorraine, additional, Strober, Michael, additional, Tortorella, Alfonso, additional, Tozzi, Federica, additional, Treasure, Janet, additional, Tziouvas, Konstantinos, additional, van Elburg, Annemarie A., additional, Wade, Tracey D., additional, Wagner, Gudrun, additional, Walton, Esther, additional, Watson, Hunna J., additional, Wichmann, H-Erich, additional, Woodside, D. Blake, additional, Zeggini, Eleftheria, additional, Zerwas, Stephanie, additional, Zipfel, Stephan, additional, Adams, Mark J., additional, Andlauer, Till F.M., additional, Berger, Klaus, additional, Binder, Elisabeth B., additional, Boomsma, Dorret I., additional, Castelao, Enrique, additional, Colodro-Conde, Lucía, additional, Direk, Nese, additional, Docherty, Anna R., additional, Domenici, Enrico, additional, Domschke, Katharina, additional, Dunn, Erin C., additional, Foo, Jerome C., additional, de. Geus, E.J.C., additional, Grabe, Hans J., additional, Hamilton, Steven P., additional, Horn, Carsten, additional, Hottenga, Jouke-Jan, additional, Howard, David, additional, Ising, Marcus, additional, Kloiber, Stefan, additional, Levinson, Douglas F., additional, Lewis, Glyn, additional, Magnusson, Patrik K.E., additional, Mbarek, Hamdi, additional, Middeldorp, Christel M., additional, Mostafavi, Sara, additional, Nyholt, Dale R., additional, Penninx, Brenda WJH., additional, Peterson, Roseann E., additional, Pistis, Giorgio, additional, Porteous, David J., additional, Preisig, Martin, additional, Quiroz, Jorge A., additional, Schaefer, Catherine, additional, Schulte, Eva C., additional, Shi, Jianxin, additional, Smith, Daniel J., additional, Thomson, Pippa A., additional, Tiemeier, Henning, additional, Uher, Rudolf, additional, van der Auwera, Sandra, additional, Weissman, Myrna M., additional, Alexander, Madeline, additional, Begemann, Martin, additional, Bramon, Elvira, additional, Buccola, Nancy G., additional, Cairns, Murray J., additional, Campion, Dominique, additional, Carr, Vaughan J., additional, Cloninger, C. Robert, additional, Cohen, David, additional, Collier, David A., additional, Corvin, Aiden, additional, DeLisi, Lynn E., additional, Donohoe, Gary, additional, Dudbridge, Frank, additional, Duan, Jubao, additional, Freedman, Robert, additional, Gejman, Pablo V., additional, Golimbet, Vera, additional, Godard, Stephanie, additional, Ehrenreich, Hannelore, additional, Hartmann, Annette M., additional, Henskens, Frans A., additional, Ikeda, Masashi, additional, Iwata, Nakao, additional, Jablensky, Assen V., additional, Joa, Inge, additional, Jönsson, Erik G., additional, Kelly, Brian J., additional, Knight, Jo, additional, Konte, Bettina, additional, Laurent-Levinson, Claudine, additional, Lee, Jimmy, additional, Lencz, Todd, additional, Lerer, Bernard, additional, Loughland, Carmel M., additional, Malhotra, Anil K., additional, Mallet, Jacques, additional, McDonald, Colm, additional, Mitjans, Marina, additional, Mowry, Bryan J., additional, Murphy, Kieran C., additional, Murray, Robin M., additional, O’Neill, F. Anthony, additional, Oh, Sang-Yun, additional, Palotie, Aarno, additional, Pantelis, Christos, additional, Pulver, Ann E., additional, Petryshen, Tracey L., additional, Quested, Digby J., additional, Riley, Brien, additional, Sanders, Alan R., additional, Schall, Ulrich, additional, Schwab, Sibylle G., additional, Scott, Rodney J., additional, Sham, Pak C., additional, Silverman, Jeremy M., additional, Sim, Kang, additional, Steixner, Agnes A., additional, Tooney, Paul A., additional, van Os, Jim, additional, Vawter, Marquis P., additional, Walsh, Dermot, additional, Weiser, Mark, additional, Wildenauer, Dieter B., additional, Williams, Nigel M., additional, Wormley, Brandon K., additional, Zhang, Fuquan, additional, Androutsos, Christos, additional, Arnold, Paul D., additional, Barr, Cathy L., additional, Barta, Csaba, additional, Bey, Katharina, additional, Bienvenu, O. Joseph, additional, Black, Donald W., additional, Brown, Lawrence W., additional, Budman, Cathy, additional, Cath, Danielle, additional, Cheon, Keun-Ah, additional, Ciullo, Valentina, additional, Coffey, Barbara J., additional, Cusi, Daniele, additional, Davis, Lea K., additional, Denys, Damiaan, additional, Depienne, Christel, additional, Dietrich, Andrea, additional, Eapen, Valsamma, additional, Falkai, Peter, additional, Fernandez, Thomas V., additional, Garcia-Delgar, Blanca, additional, Geller, Daniel A., additional, Gilbert, Donald L., additional, Grados, Marco A., additional, Greenberg, Erica, additional, Grünblatt, Edna, additional, Hagstrøm, Julie, additional, Hanna, Gregory L., additional, Hartmann, Andreas, additional, Hedderly, Tammy, additional, Heiman, Gary A., additional, Heyman, Isobel, additional, Hong, Hyun Ju, additional, Huang, Alden, additional, Huyser, Chaim, additional, Ibanez-Gomez, Laura, additional, Khramtsova, Ekaterina A., additional, Kim, Young Key, additional, Kim, Young-Shin, additional, King, Robert A., additional, Koh, Yun-Joo, additional, Konstantinidis, Anastasios, additional, Kook, Sodahm, additional, Kuperman, Samuel, additional, Leventhal, Bennett L., additional, Lochner, Christine, additional, Ludolph, Andrea G., additional, Madruga-Garrido, Marcos, additional, Malaty, Irene, additional, Maras, Athanasios, additional, McCracken, James T., additional, Meijer, Inge A., additional, Mir, Pablo, additional, Morer, Astrid, additional, Müller-Vahl, Kirsten R., additional, Münchau, Alexander, additional, Murphy, Tara L., additional, Naarden, Allan, additional, Nagy, Peter, additional, Nestadt, Gerald, additional, Nestadt, Paul S., additional, Nicolini, Humberto, additional, Nurmi, Erika L., additional, Okun, Michael S., additional, Paschou, Peristera, additional, Piras, Fabrizio, additional, Piras, Federica, additional, Pittenger, Christopher, additional, Plessen, Kerstin J., additional, Richter, Margaret A., additional, Rizzo, Renata, additional, Robertson, Mary, additional, Roessner, Veit, additional, Ruhrmann, Stephan, additional, Samuels, Jack F., additional, Sandor, Paul, additional, Schlögelhofer, Monika, additional, Shin, Eun-Young, additional, Singer, Harvey, additional, Song, Dong-Ho, additional, Song, Jungeun, additional, Spalletta, Gianfranco, additional, Stein, Dan J., additional, Stewart, S Evelyn, additional, Storch, Eric A., additional, Stranger, Barbara, additional, Stuhrmann, Manfred, additional, Tarnok, Zsanett, additional, Tischfield, Jay A., additional, Tübing, Jennifer, additional, Visscher, Frank, additional, Vulink, Nienke, additional, Wagner, Michael, additional, Walitza, Susanne, additional, Wanderer, Sina, additional, Woods, Martin, additional, Worbe, Yulia, additional, Zai, Gwyneth, additional, Zinner, Samuel H., additional, Sullivan, Patrick F., additional, Franke, Barbara, additional, Daly, Mark J., additional, Bulik, Cynthia M., additional, McIntosh, Andrew M., additional, O’Donovan, Michael C., additional, Zheutlin, Amanda, additional, Andreassen, Ole A., additional, Børglum, Anders D., additional, Breen, Gerome, additional, Edenberg, Howard J., additional, Fanous, Ayman H., additional, Faraone, Stephen V., additional, Gelernter, Joel, additional, Mathews, Carol A., additional, Mattheisen, Manuel, additional, Mitchell, Karen S., additional, Neale, Michael C., additional, Nurnberger, John I., additional, Ripke, Stephan, additional, Santangelo, Susan L., additional, Scharf, Jeremiah M., additional, Stein, Murray B., additional, Thornton, Laura M., additional, Walters, James T.R., additional, Wray, Naomi R., additional, Geschwind, Daniel H., additional, Neale, Benjamin M., additional, Kendler, Kenneth S., additional, and Smoller, Jordan W., additional

Published
2019
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27. Characterising the loss-of-function impact of 5' untranslated region variants in 15,708 individuals

Author

Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, Whiffin, Nicola, Karczewski, Konrad J., Zhang, Xiaolei, Chothani, Sonia, Smith, Miriam J., Evans, D. Gareth, Roberts, Angharad M., Quaife, Nicholas M., Schafer, Sebastian, Rackham, Owen, Alföldi, Jessica, O’Donnell-Luria, Anne H., Francioli, Laurent C., Armean, Irina M., Banks, Eric, Bergelson, Louis, Cibulskis, Kristian, Collins, Ryan L., Connolly, Kristen M., Covarrubias, Miguel, Cummings, Beryl, Daly, Mark J., Donnelly, Stacey, Farjoun, Yossi, Ferriera, Steven, Gabriel, Stacey, Gauthier, Laura D., Gentry, Jeff, Gupta, Namrata, Jeandet, Thibault, Kaplan, Diane, Laricchia, Kristen M., Llanwarne, Christopher, Minikel, Eric V., Munshi, Ruchi, Neale, Benjamin M., Novod, Sam, Petrillo, Nikelle, Poterba, Timothy, Roazen, David, Ruano-Rubio, Valentin, Saltzman, Andrea, Samocha, Kaitlin E., Schleicher, Molly, Seed, Cotton, Solomonson, Matthew, Soto, Jose, Lehtimäki, Terho, Mattila, Kari M., Suvisaari, Jaana, Imper, Rosetrees Trust, Wellcome Trust, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Department of Medicine, Clinicum, Gastroenterologian yksikkö, Institute for Molecular Medicine Finland, Biosciences, Genomics of Neurological and Neuropsychiatric Disorders, HUS Psychiatry, Department of Psychiatry, HUS Neurocenter, Department of Neurosciences, Neurologian yksikkö, Department of Public Health, Research Programme of Molecular Medicine, Aarno Palotie / Principal Investigator, Doctoral Programme in Social Sciences, Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, University Management, Biostatistics Helsinki, Faculty of Medicine, University of Helsinki, Tampere University, Clinical Medicine, Department of Clinical Chemistry, BioMediTech, Fondation Leducq, Department of Health, Leducq Foundation for Cardiovascular Research, British Heart Foundation, and Royal Brompton & Harefield NHS Foundation Trust

Subjects
0301 basic medicine, Untranslated region, Five prime untranslated region, General Physics and Astronomy, Genome informatics, Negative selection, 0302 clinical medicine, Loss of Function Mutation, Genetics research, Coding region, lcsh:Science, education.field_of_study, Multidisciplinary, 1184 Genetics, developmental biology, physiology, Genome Aggregation Database Production Team, Genomics, Multidisciplinary Sciences, Genome Aggregation Database (gnomAD) Consortium, Science & Technology - Other Topics, 5'-UNTRANSLATED REGIONS, Medical genomics, Genome Aggregation Database (gnomAD) Production Team, OPEN READING FRAMES, Science, Population, WOUDE, Computational biology, Biology, Article, General Biochemistry, Genetics and Molecular Biology, ORFS, Frameshift mutation, 03 medical and health sciences, Humans, Author Correction, education, Gene, Science & Technology, Base Sequence, Genome, Human, MUTATIONS, Genetic Variation, Proteins, General Chemistry, 030104 developmental biology, INITIATION CODON, Genome Aggregation Database Consortium, Human genome, lcsh:Q, 3111 Biomedicine, TRANSLATION, 5' Untranslated Regions, 030217 neurology & neurosurgery, VAN
Abstract

Upstream open reading frames (uORFs) are tissue-specific cis-regulators of protein translation. Isolated reports have shown that variants that create or disrupt uORFs can cause disease. Here, in a systematic genome-wide study using 15,708 whole genome sequences, we show that variants that create new upstream start codons, and variants disrupting stop sites of existing uORFs, are under strong negative selection. This selection signal is significantly stronger for variants arising upstream of genes intolerant to loss-of-function variants. Furthermore, variants creating uORFs that overlap the coding sequence show signals of selection equivalent to coding missense variants. Finally, we identify specific genes where modification of uORFs likely represents an important disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in neurofibromatosis. Our results highlight uORF-perturbing variants as an under-recognised functional class that contribute to penetrant human disease, and demonstrate the power of large-scale population sequencing data in studying non-coding variant classes., Upstream open reading frames (uORFs), located in 5’ untranslated regions, are regulators of downstream protein translation. Here, Whiffin et al. use the genomes of 15,708 individuals in the Genome Aggregation Database (gnomAD) to systematically assess the deleteriousness of variants creating or disrupting uORFs.

Published
2019

28. Transcript expression-aware annotation improves rare variant discovery and interpretation

Author

Cummings, Beryl B., Karczewski, Konrad J., Kosmicki, Jack A., Seaby, Eleanor G., Watts, Nicholas A., Singer-Berk, Moriel, Mudge, Jonathan M., Karjalainen, Juha, Satterstrom, F. Kyle, O’Donnell-Luria, Anne, Poterba, Timothy, Seed, Cotton, Solomonson, Matthew, Alföldi, Jessica, Daly, Mark J., and MacArthur, Daniel G.

Subjects
0303 health sciences, 03 medical and health sciences, Annotation, 0302 clinical medicine, Computational biology, Biology, 030217 neurology & neurosurgery, 030304 developmental biology, Gene transcript, Interpretation (model theory)
Abstract

The acceleration of DNA sequencing in patients and population samples has resulted in unprecedented catalogues of human genetic variation, but the interpretation of rare genetic variants discovered using such technologies remains extremely challenging. A striking example of this challenge is the existence of disruptive variants in dosage-sensitive disease genes, even in apparently healthy individuals. Through manual curation of putative loss of function (pLoF) variants in haploinsufficient disease genes in the Genome Aggregation Database (gnomAD)(1), we show that one explanation for this paradox involves alternative mRNA splicing, which allows exons of a gene to be expressed at varying levels across cell types. Currently, no existing annotation tool systematically incorporates this exon expression information into variant interpretation. Here, we develop a transcript-level annotation metric, the proportion expressed across transcripts (pext), which summarizes isoform quantifications for variants. We calculate this metric using 11,706 tissue samples from the Genotype Tissue Expression project(2) (GTEx) and show that it clearly differentiates between weakly and highly evolutionarily conserved exons, a proxy for functional importance. We demonstrate that expression-based annotation selectively filters 22.8% of falsely annotated pLoF variants found in haploinsufficient disease genes in gnomAD, while removing less than 4% of high-confidence pathogenic variants in the same genes. Finally, we apply our expression filter to the analysis of de novo variants in patients with autism spectrum disorder (ASD) and developmental disorders and intellectual disability (DD/ID) to show that pLoF variants in weakly expressed regions have effect sizes similar to those of synonymous variants, while pLoF variants in highly expressed exons are most strongly enriched among cases versus controls. Our annotation is fast, flexible, and generalizable, making it possible for any variant file to be annotated with any isoform expression dataset, and will be valuable for rare disease diagnosis, rare variant burden analyses in complex disorders, and curation and prioritization of variants in recall-by-genotype studies.

Published
2019

29. Characterising the loss-of-function impact of 5’ untranslated region variants in whole genome sequence data from 15,708 individuals

Author

Whiffin, Nicola, Karczewski, Konrad J, Zhang, Xiaolei, Chothani, Sonia, Smith, Miriam J, Evans, D Gareth, Roberts, Angharad M, Quaife, Nicholas M, Schafer, Sebastian, Rackham, Owen, Alföldi, Jessica, O’Donnell-Luria, Anne H, Francioli, Laurent C, Armean, Irina M., Banks, Eric, Bergelson, Louis, Cibulskis, Kristian, Collins, Ryan L, Connolly, Kristen M., Covarrubias, Miguel, Cummings, Beryl, Daly, Mark J., Donnelly, Stacey, Farjoun, Yossi, Ferriera, Steven, Francioli, Laurent, Gabriel, Stacey, Gauthier, Laura D., Gentry, Jeff, Gupta, Namrata, Jeandet, Thibault, Kaplan, Diane, Karczewski, Konrad J., Laricchia, Kristen M., Llanwarne, Christopher, Minikel, Eric V., Munshi, Ruchi, Neale, Benjamin M, Novod, Sam, O’Donnell-Luria, Anne H., Petrillo, Nikelle, Poterba, Timothy, Roazen, David, Ruano-Rubio, Valentin, Saltzman, Andrea, Samocha, Kaitlin E., Schleicher, Molly, Seed, Cotton, Solomonson, Matthew, Soto, Jose, Tiao, Grace, Tibbetts, Kathleen, Tolonen, Charlotte, Vittal, Christopher, Wade, Gordon, Wang, Arcturus, Wang, Qingbo, Ware, James S, Watts, Nicholas A, Weisburd, Ben, Salinas, Carlos A Aguilar, Ahmad, Tariq, Albert, Christine M., Ardissino, Diego, Atzmon, Gil, Barnard, John, Beaugerie, Laurent, Benjamin, Emelia J., Boehnke, Michael, Bonnycastle, Lori L., Bottinger, Erwin P., Bowden, Donald W, Bown, Matthew J, Chambers, John C, Chan, Juliana C., Chasman, Daniel, Cho, Judy, Chung, Mina K., Cohen, Bruce, Correa, Adolfo, Dabelea, Dana, Darbar, Dawood, Duggirala, Ravindranath, Dupuis, Josée, Ellinor, Patrick T., Elosua, Roberto, Erdmann, Jeanette, Esko, Tõnu, Färkkilä, Martti, Florez, Jose, Franke, Andre, Getz, Gad, Glaser, Benjamin, Glatt, Stephen J., Goldstein, David, Gonzalez, Clicerio, Groop, Leif, Haiman, Christopher, Hanis, Craig, Harms, Matthew, Hiltunen, Mikko, Holi, Matti M., Hultman, Christina M., Kallela, Mikko, Kaprio, Jaakko, Kathiresan, Sekar, Kim, Bong-Jo, Kim, Young Jin, Kirov, George, Kooner, Jaspal, Koskinen, Seppo, Krumholz, Harlan M., Kugathasan, Subra, Kwak, Soo Heon, Laakso, Markku, Lehtimäki, Terho, Loos, Ruth J.F., Lubitz, Steven A., Ma, Ronald C.W., MacArthur, Daniel G., Marrugat, Jaume, Mattila, Kari M., McCarroll, Steven, McCarthy, Mark I, McGovern, Dermot, McPherson, Ruth, Meigs, James B., Melander, Olle, Metspalu, Andres, Nilsson, Peter M, O’Donovan, Michael C, Ongur, Dost, Orozco, Lorena, Owen, Michael J, Palmer, Colin N.A., Palotie, Aarno, Park, Kyong Soo, Pato, Carlos, Pulver, Ann E., Rahman, Nazneen, Remes, Anne M., Rioux, John D., Ripatti, Samuli, Roden, Dan M., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Scharf, Jeremiah, Schunkert, Heribert, Shoemaker, Moore B., Sklar, Pamela, Soininen, Hilkka, Soko, Harry, Spector, Tim, Sullivan, Patrick F., Suvisaari, Jaana, Tai, E Shyong, Teo, Yik Ying, Tiinamaija, Tuomi, Tsuang, Ming, Turner, Dan, Tusie-Luna, Teresa, Vartiainen, Erkki, Watkins, Hugh, Weersma, Rinse K, Wessman, Maija, Wilson, James G., Xavier, Ramnik J., Cook, Stuart A, Barton, Paul J R, and MacArthur, Daniel G

Subjects
0303 health sciences, education.field_of_study, Five prime untranslated region, Population, Computational biology, Biology, Genome, DNA sequencing, Frameshift mutation, 03 medical and health sciences, Negative selection, 0302 clinical medicine, Coding region, education, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Upstream open reading frames (uORFs) are important tissue-specific cis-regulators of protein translation. Although isolated case reports have shown that variants that create or disrupt uORFs can cause disease, genetic sequencing approaches typically focus on protein-coding regions and ignore these variants. Here, we describe a systematic genome-wide study of variants that create and disrupt human uORFs, and explore their role in human disease using 15,708 whole genome sequences collected by the Genome Aggregation Database (gnomAD) project. We show that 14,897 variants that create new start codons upstream of the canonical coding sequence (CDS), and 2,406 variants disrupting the stop site of existing uORFs, are under strong negative selection. Furthermore, variants creating uORFs that overlap the CDS show signals of selection equivalent to coding loss-of-function variants, and uORF-perturbing variants are under strong selection when arising upstream of known disease genes and genes intolerant to loss-of-function variants. Finally, we identify specific genes where perturbation of uORFs is likely to represent an important disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in families with neurofibromatosis. Our results highlight uORF-perturbing variants as an important and under-recognised functional class that can contribute to penetrant human disease, and demonstrate the power of large-scale population sequencing data to study the deleteriousness of specific classes of non-coding variants.

Published
2019
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30. Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes

Author

Karczewski, Konrad J., Francioli, Laurent C., Tiao, Grace, Cummings, Beryl B., Alföldi, Jessica, Wang, Qingbo, Collins, Ryan L., Laricchia, Kristen M., Ganna, Andrea, Birnbaum, Daniel P., Gauthier, Laura D., Brand, Harrison, Solomonson, Matthew, Watts, Nicholas A., Rhodes, Daniel, Singer-Berk, Moriel, Seaby, Eleanor G., Kosmicki, Jack A., Walters, Raymond K., Tashman, Katherine, Farjoun, Yossi, Banks, Eric, Poterba, Timothy, Wang, Arcturus, Seed, Cotton, Whiffin, Nicola, Chong, Jessica X., Samocha, Kaitlin E., Pierce-Hoffman, Emma, Zappala, Zachary, O’Donnell-Luria, Anne H., Minikel, Eric Vallabh, Weisburd, Ben, Lek, Monkol, Ware, James S., Vittal, Christopher, Armean, Irina M., Bergelson, Louis, Cibulskis, Kristian, Connolly, Kristen M., Covarrubias, Miguel, Donnelly, Stacey, Ferriera, Steven, Gabriel, Stacey, Gentry, Jeff, Gupta, Namrata, Jeandet, Thibault, Kaplan, Diane, Llanwarne, Christopher, Munshi, Ruchi, Novod, Sam, Petrillo, Nikelle, Roazen, David, Ruano-Rubio, Valentin, Saltzman, Andrea, Schleicher, Molly, Soto, Jose, Tibbetts, Kathleen, Tolonen, Charlotte, Wade, Gordon, Talkowski, Michael E., Neale, Benjamin M., Daly, Mark J., and MacArthur, Daniel G.

Abstract

Summary Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes critical for an organism’s function will be depleted for such variants in natural populations, while non-essential genes will tolerate their accumulation. However, predicted loss-of-function (pLoF) variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes. Here, we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence pLoF variants in this cohort after filtering for sequencing and annotation artifacts. Using an improved model of human mutation, we classify human protein-coding genes along a spectrum representing intolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve gene discovery power for both common and rare diseases.

Published
2019
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31. Genomic Relationships, Novel Loci, And Pleiotropic Mechanisms Across Eight Psychiatric Disorders

Author

Lee, Phil H., Anttila, Verneri, Won, Hyejung, Feng, Yen-Chen A., Rosenthal, Jacob, Zhu, Zhaozhong, Tucker-Drob, Elliot M., Nivard, Michel G., Grotzinger, Andrew D., Posthuma, Danielle, Wang, Meg M.-J., Yu, Dongmei, Stahl, Eli A., Walters, Raymond K., Anney, Richard J.L., Duncan, Laramie E., Ge, Tian, Adolfsson, Rolf, Banaschewski, Tobias, Belangero, Sintia, Cook, Edwin H., Coppola, Giovanni, Derks, Eske M., Hoekstra, Pieter J., Kaprio, Jaakko, Keski-Rahkonen, Anna, Kirov, George, Kranzler, Henry R., Luykx, Jurjen J., Rohde, Luis A., Zai, Clement C., Agerbo, Esben, Arranz, M.J., Asherson, Philip, Bækvad-Hansen, Marie, Baldursson, Gísli, Bellgrove, Mark, Belliveau, Richard A., Buitelaar, Jan, Burton, Christie L., Bybjerg-Grauholm, Jonas, Casas, Miquel, Cerrato, Felecia, Chambert, Kimberly, Churchhouse, Claire, Cormand, Bru, Crosbie, Jennifer, Dalsgaard, Søren, Demontis, Ditte, Doyle, Alysa E., Dumont, Ashley, Elia, Josephine, Grove, Jakob, Gudmundsson, Olafur O., Haavik, Jan, Hakonarson, Hakon, Hansen, Christine S., Hartman, Catharina A., Hawi, Ziarih, Hervás, Amaia, Hougaard, David M., Howrigan, Daniel P., Huang, Hailiang, Kuntsi, Jonna, Langley, Kate, Lesch, Klaus-Peter, Leung, Patrick W.L., Loo, Sandra K., Martin, Joanna, Martin, Alicia R., McGough, James J., Medland, Sarah E., Moran, Jennifer L., Mors, Ole, Mortensen, Preben B., Oades, Robert D., Palmer, Duncan S., Pedersen, Carsten B., Pedersen, Marianne G., Peters, Triinu, Poterba, Timothy, Poulsen, Jesper B., Ramos-Quiroga, Josep Antoni, Reif, Andreas, Ribasés, Marta, Rothenberger, Aribert, Rovira, Paula, Sánchez-Mora, Cristina, Satterstrom, F. Kyle, Schachar, Russell, Artigas, Maria Soler, Steinberg, Stacy, and Weissman, Myrna M.

Published
2019
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32. A genetic investigation of sex bias in the prevalence of attention-deficit/hyperactivity disorder

Author

Martin, Joanna, Walters, Raymond K., Demontis, Ditte, Mattheisen, Manuel, Lee, S. Hong, Robinson, Elise, Brikell, Isabell, Ghirardi, Laura, Larsson, Henrik, Lichtenstein, Paul, Eriksson, Nicholas, Werge, Thomas, Mortensen, Preben Bo, Pedersen, Marianne Giørtz, Mors, Ole, Nordentoft, Merete, Hougaard, David M., Bybjerg-Grauholm, Jonas, Wray, Naomi R., Franke, Barbara, Faraone, Stephen V., O'Donovan, Michael, Thapar, Anita, Børglum, Anders D., Neale, Benjamin M., Agee, Michelle, Alipanahi, Babak, Auton, Adam, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Fontanillas, Pierre, Furlotte, Nicholas A., Hinds, David A., Hromatka, Bethann S., Huber, Karen E., Kleinman, Aaron, Litterman, Nadia K., McIntyre, Matthew H., Mountain, Joanna L., Northover, Carrie A.M., Pitts, Steven J., Sathirapongsasuti, J. Fah, Sazonova, Olga V., Shelton, Janie F., Shringarpure, Suyash, Tian, Chao, Tung, Joyce Y., Vacic, Vladimir, Wilson, Catherine H., Albayrak, Özgür, Anney, Richard J. L., Vasquez, Alejandro Arias, Arranz, Maria Jesús, Asherson, Philip, Banaschewski, Tobias, Banaschewski, Tobias J., Bau, Claiton, Biederman, Joseph, Buitelaar, Jan K., Casas, Miguel, Charach, Alice, Cormand, Bru, Crosbie, Jennifer, Dalsgaard, Soeren, Daly, Mark J., Dempfle, Astrid, Doyle, Alysa E., Ebstein, Richard P., Elia, Josephine, Föcker, Manuel, Freitag, Christine, Gelernter, Joel, Gill, Michael, Grevet, Eugenio, Haavik, Jan, Hakonarson, Hakon, Hawi, Ziarih, Hebebrand, Johannes, Herpertz-Dahlmann, Beate, Hervas, Amaia, Hinney, Anke, Hohmann, Sarah, Holmans, Peter, Hutz, Mara, Ickowitz, Abel, Johansson, Stefan, Kent, Lindsey, Kittel-Schneider, Sarah, Kranzler, Henry, Kuntsi, Jonna, Lambregts-Rommelse, Nanda, Langley, Kate, Lehmkuhl, Gerd, Lesch, Klaus-Peter, Loo, Sandra K., McGough, James J., Medland, Sarah E., Meyer, Jobst, Mick, Eric, Middletion, Frank, Miranda, Ana, Mulas, Fernando, Mulligan, Aisling, Nelson, Stan F., Nguyen, T. Trang, Oades, Robert D., Palmason, Haukur, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Renner, Tobias J., Rhode, Luis, Ribasés, Marta, Rietschel, Marcella, Ripke, Stephan, Rivero, Olga, Sánchez-Mora, Cristina, Schachar, Russell, Schäfer, Helmut, Scherag, André, Schimmelmann, Benno G., Sergeant, Joseph, Sinzig, Judith, Smalley, Susan L., Sonuga-Barke, Edmund J.S., Steinhausen, Hans-Christoph, Sullivan, Patrick F., Thompsom, Margaret, Todorov, Alexandre, Waldman, Irwin, Walitza, Susanne, Wang, Yufeng, Warnke, Andreas, Williams, Nigel, Witt, Stephanie H., Yang, Li, Zayats, Tetyana, Zhang-James, Yanli, Agerbo, Esben, Damm Als, Thomas, Bækved-Hansen, Marie, Belliveau, Rich, Cerrato, Felecia, Chambert, Kimberly, Churchhouse, Claire, Dalsgaard, Søren, Dumont, Ashley, Goldstein, Jacqueline, Grove, Jakob, Hansen, Christine S., Engel Hauberg, Mads, Hollegaard, Mads V., Howrigan, Daniel P., Huang, Hailiang, Maller, Julian, Martin, Alicia R., Moran, Jennifer, Pallesen, Jonatan, Palmer, Duncan S., Pedersen, Carsten Bøcker, Poterba, Timothy, Poulson, Jesper Buchhave, Robinson, Elise B., Satterstrom, F. Kyle, Stevens, Christine, and Turley, Patrick

Abstract

Background Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is 2-7 times more common in males than females. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. Methods We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (20,183 cases, 35,191 controls) and Swedish populationregister data (N=77,905 cases, N=1,874,637 population controls). Results Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with rg estimates close to 1. Analyses of population data, however, indicated that females with ADHD may be at especially high risk of certain comorbid developmental conditions (i.e. autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score (PRS) analysis did not support a higher burden of ADHD common risk variants in female cases (OR=1.02 [0.98-1.06], p=0.28). In contrast, epidemiological sibling analyses revealed that the siblings of females with ADHD are at higher familial risk of ADHD than siblings of affected males (OR=1.14, [95% CI: 1.11-1.18], p=1.5E-15). Conclusions Overall, this study supports a greater familial burden of risk in females with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence.

Published
2018

33. Bayesian model comparison for rare variant association studies of multiple phenotypes

Author

DeBoever, Christopher, Aguirre, Matthew, Tanigawa, Yosuke, Spencer, Chris C. A., Poterba, Timothy, Bustamante, Carlos D., Daly, Mark J., Pirinen, Matti, and Rivas, Manuel A.

Abstract

Whole genome sequencing studies applied to large populations or biobanks with extensive phenotyping raise new analytic challenges. The need to consider many variants at a locus or group of genes simultaneously and the potential to study many correlated phenotypes with shared genetic architecture provide opportunities for discovery and inference that are not addressed by the traditional one variant-one phenotype association study. Here we introduce a model comparison approach we refer to as MRP for rare variant association studies that considers correlation, scale, and location of genetic effects across a group of genetic variants, phenotypes, and studies. We consider the use of summary statistic data to apply univariate and multivariate gene-based meta-analysis models for identifying rare variant associations with an emphasis on protective protein-truncating variants that can expedite drug discovery. Through simulation studies, we demonstrate that the proposed model comparison approach can improve ability to detect rare variant association signals. We also apply the model to two groups of phenotypes from the UK Biobank: 1) asthma diagnosis, eosinophil counts, forced expiratory volume, and forced vital capacity; and 2) glaucoma diagnosis, intra-ocular pressure, and corneal resistance factor. We are able to recover known associations such as the protective association between rs146597587 in IL33 and asthma. We also find evidence for novel protective associations between rare variants in ANGPTL7 and glaucoma. Overall, we show that the MRP model comparison approach is able to retain and improve upon useful features from widely-used meta-analysis approaches for rare variant association analyses and prioritize protective modifiers of disease risk. Author summary Due to the continually decreasing cost of acquiring genetic data, we are now beginning to see large collections of individuals for which we have both genetic information and trait data such as disease status, physical measurements, biomarker levels, and more. These datasets offer new opportunities to find relationships between inherited genetic variation and disease. While it is known that there are relationships between different traits, typical genetic analyses only focus on analyzing one genetic variant and one phenotype at a time. Additionally, it is difficult to identify rare genetic variants that are associated with disease due to their scarcity, even among large sample sizes. In this work, we present a method for identifying associations between genetic variation and disease that considers multiple rare variants and phenotypes at the same time. By sharing information across rare variant and phenotypes, we improve our ability to identify rare variants associated with disease compared to considering a single rare variant and a single phenotype. The method can be used to identify candidate disease genes as well as genes that might represent attractive drug targets.

Published
2018
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34. Discovery of the first genome-wide significant risk loci for ADHD

Author

Demontis, Ditte, Walters, Raymond K., Martin, Joanna, Mattheisen, Manuel, Als, Thomas D., Agerbo, Esben, Belliveau, Rich, Bybjerg-Grauholm, Jonas, Bækvad-Hansen, Marie, Cerrato, Felecia, Chambert, Kimberly, Churchhouse, Claire, Dumont, Ashley, Eriksson, Nicholas, Gandal, Michael, Goldstein, Jacqueline, Grove, Jakob, Hansen, Christine S., Hauberg, Mads E., Hollegaard, Mads V., Howrigan, Daniel P., Huang, Hailiang, Maller, Julian, Martin, Alicia R., Moran, Jennifer, Pallesen, Jonatan, Palmer, Duncan S., Pedersen, Carsten B., Pedersen, Marianne G., Poterba, Timothy, Poulsen, Jesper B., Ripke, Stephan, Robinson, Elise B., Satterstrom, Kyle F., Stevens, Christine, Turley, Patrick, Won, Hyejung, Andreassen, Ole A., Burton, Christie, Boomsma, Dorret, Cormand, Bru, Dalsgaard, Søren, Franke, Barbara, Gelernter, Joel, Geschwind, Daniel, Hakonarson, Hakon, Haavik, Jan, Kranzler, Henry, Kuntsi, Jonna, Langley, Kate, Lesch, Klaus-Peter, Middeldorp, Christel, Reif, Andreas, Rohde, Luis A., Roussos, Panos, Schachar, Russell, Sklar, Pamela, Sonuga-Barke, Edmund, Sullivan, Patrick F., Thapar, Anita, Tung, Joyce, Waldman, Irwin, Nordentoft, Merete, Hougaard, David M., Werge, Thomas, Mors, Ole, Mortensen, Preben B., Daly, Mark J., Faraone, Stephen V., Børglum, Anders D., and Neale, Benjamin M.

Subjects
Genetics, 0303 health sciences, education.field_of_study, Population, Genetic variants, Biology, Genome, behavioral disciplines and activities, 3. Good health, 03 medical and health sciences, Behavior disorder, 0302 clinical medicine, Clinical diagnosis, mental disorders, Adhd symptoms, Significant risk, education, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of school-age children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no individual variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 ADHD cases and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, revealing new and important information on the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes, as well as around brain-expressed regulatory marks. These findings, based on clinical interviews and/or medical records are supported by additional analyses of a self-reported ADHD sample and a study of quantitative measures of ADHD symptoms in the population. Meta-analyzing these data with our primary scan yielded a total of 16 genome-wide significant loci. The results support the hypothesis that clinical diagnosis of ADHD is an extreme expression of one or more continuous heritable traits.

Published
2017
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35. Transcript expression-aware annotation improves rare variant interpretation.

Author

Cummings, Beryl B., Karczewski, Konrad J., Kosmicki, Jack A., Seaby, Eleanor G., Watts, Nicholas A., Singer-Berk, Moriel, Mudge, Jonathan M., Karjalainen, Juha, Satterstrom, F. Kyle, O'Donnell-Luria, Anne H., Poterba, Timothy, Seed, Cotton, Solomonson, Matthew, Alföldi, Jessica, Genome Aggregation Database Production Team, Armean, Irina M., Banks, Eric, Bergelson, Louis, Cibulskis, Kristian, and Collins, Ryan L.

Abstract

The acceleration of DNA sequencing in samples from patients and population studies has resulted in extensive catalogues of human genetic variation, but the interpretation of rare genetic variants remains problematic. A notable example of this challenge is the existence of disruptive variants in dosage-sensitive disease genes, even in apparently healthy individuals. Here, by manual curation of putative loss-of-function (pLoF) variants in haploinsufficient disease genes in the Genome Aggregation Database (gnomAD)1, we show that one explanation for this paradox involves alternative splicing of mRNA, which allows exons of a gene to be expressed at varying levels across different cell types. Currently, no existing annotation tool systematically incorporates information about exon expression into the interpretation of variants. We develop a transcript-level annotation metric known as the 'proportion expressed across transcripts', which quantifies isoform expression for variants. We calculate this metric using 11,706 tissue samples from the Genotype Tissue Expression (GTEx) project2 and show that it can differentiate between weakly and highly evolutionarily conserved exons, a proxy for functional importance. We demonstrate that expression-based annotation selectively filters 22.8% of falsely annotated pLoF variants found in haploinsufficient disease genes in gnomAD, while removing less than 4% of high-confidence pathogenic variants in the same genes. Finally, we apply our expression filter to the analysis of de novo variants in patients with autism spectrum disorder and intellectual disability or developmental disorders to show that pLoF variants in weakly expressed regions have similar effect sizes to those of synonymous variants, whereas pLoF variants in highly expressed exons are most strongly enriched among cases. Our annotation is fast, flexible and generalizable, making it possible for any variant file to be annotated with any isoform expression dataset, and will be valuable for the genetic diagnosis of rare diseases, the analysis of rare variant burden in complex disorders, and the curation and prioritization of variants in recall-by-genotype studies. A novel variant annotation metric that quantifies the level of expression of genetic variants across tissues is validated in the Genome Aggregation Database (gnomAD) and is shown to improve rare variant interpretation. [ABSTRACT FROM AUTHOR]

Published
2020
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37. Genome-Wide Association Study of Hematoma Volume Identifies 17p12 as a Novel Susceptibility Locus for Severity and Outcome in Intracerebral Hemorrhage (S1.002)

Author

Marini, Sandro, primary, Devan, William J., additional, Radmanesh, Farid, additional, Miyares, Laura, additional, Poterba, Timothy, additional, Hansen, Bjorn, additional, Norrving, Bo, additional, Giralt-Steinhauer, Eva, additional, Jimenez-Conde, Jordi, additional, Elosua, Roberto, additional, Cuadrado-Godia, Elisa, additional, Soriano, Carolina, additional, Gonzalez, Jaume Roquer, additional, Kourkoulis, Christina, additional, Ayres, Alison M., additional, Schwab, Kristin, additional, Tirschwell, David, additional, Selim, Magdy, additional, Brown, Devin, additional, Silliman, Scott, additional, Worrall, Bradford, additional, Meschia, James, additional, Kidwell, Chelsea, additional, Montaner, Joan, additional, Fernandez-Cadenas, Israel, additional, Delgado, Pilar, additional, Greenberg, Steven, additional, Lindgren, Arne, additional, Matouk, Charles, additional, Sheth, Kevin, additional, Woo, Daniel, additional, Anderson, Christopher, additional, Rosand, Jonathan, additional, and Falcone, Guido, additional

Published
2018
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38. Bayesian model comparison for rare variant association studies

Author

Venkataraman, Guhan Ram, primary, DeBoever, Christopher, additional, Tanigawa, Yosuke, additional, Aguirre, Matthew, additional, Ioannidis, Alexander G., additional, Mostafavi, Hakhamanesh, additional, Spencer, Chris C. A., additional, Poterba, Timothy, additional, Bustamante, Carlos D., additional, Daly, Mark J., additional, Pirinen, Matti, additional, and Rivas, Manuel A., additional

Published
2018
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39. Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders

Author

Weiner, Daniel J., Wigdor, Emilie M., Ripke, Stephan, Walters, Raymond K., Kosmicki, Jack A., Grove, Jakob, Samocha, Kaitlin E., Goldstein, Jacqueline I., Okbay, Aysu, Bybjerg-Grauholm, Jonas, Werge, Thomas, Hougaard, David M., Taylor, Jacob, Skuse, David, Devlin, Bernie, Anney, Richard, Sanders, Stephan J., Bishop, Somer, Mortensen, Preben Bo, Børglum, Anders D., Smith, George Davey, Daly, Mark J., Robinson, Elise B., Bækvad-Hansen, Marie, Dumont, Ashley, Hansen, Christine, Hansen, Thomas F., Howrigan, Daniel, Mattheisen, Manuel, Moran, Jennifer, Mors, Ole, Nordentoft, Merete, Nørgaard-Pedersen, Bent, Poterba, Timothy, Poulsen, Jesper, Stevens, Christine, Anttila, Verneri, Holmans, Peter, Huang, Hailiang, Klei, Lambertus, Lee, Phil H., Medland, Sarah E., Neale, Benjamin, Weiss, Lauren A., Zwaigenbaum, Lonnie, Yu, Timothy W., Wittemeyer, Kerstin, Willsey, A. Jeremy, Wijsman, Ellen M., Wassink, Thomas H., Psychiatric Genomics Consortium Autism Group, iPSYCH-Broad Autism Group, Weiner, Daniel J., Wigdor, Emilie M., Ripke, Stephan, Walters, Raymond K., Kosmicki, Jack A., Grove, Jakob, Samocha, Kaitlin E., Goldstein, Jacqueline I., Okbay, Aysu, Bybjerg-Grauholm, Jonas, Werge, Thomas, Hougaard, David M., Taylor, Jacob, Skuse, David, Devlin, Bernie, Anney, Richard, Sanders, Stephan J., Bishop, Somer, Mortensen, Preben Bo, Børglum, Anders D., Smith, George Davey, Daly, Mark J., Robinson, Elise B., Bækvad-Hansen, Marie, Dumont, Ashley, Hansen, Christine, Hansen, Thomas F., Howrigan, Daniel, Mattheisen, Manuel, Moran, Jennifer, Mors, Ole, Nordentoft, Merete, Nørgaard-Pedersen, Bent, Poterba, Timothy, Poulsen, Jesper, Stevens, Christine, Anttila, Verneri, Holmans, Peter, Huang, Hailiang, Klei, Lambertus, Lee, Phil H., Medland, Sarah E., Neale, Benjamin, Weiss, Lauren A., Zwaigenbaum, Lonnie, Yu, Timothy W., Wittemeyer, Kerstin, Willsey, A. Jeremy, Wijsman, Ellen M., Wassink, Thomas H., Psychiatric Genomics Consortium Autism Group, and iPSYCH-Broad Autism Group

Abstract

Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.

Published
2017
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40. The mutational constraint spectrum quantified from variation in 141,456 humans

Author

Karczewski, Konrad J., Francioli, Laurent C., Tiao, Grace, Cummings, Beryl B., Alföldi, Jessica, Wang, Qingbo, Collins, Ryan L., Laricchia, Kristen M., Ganna, Andrea, Birnbaum, Daniel P., Gauthier, Laura D., Brand, Harrison, Solomonson, Matthew, Watts, Nicholas A., Rhodes, Daniel, Singer-Berk, Moriel, England, Eleina M., Seaby, Eleanor G., Kosmicki, Jack A., Walters, Raymond K., Tashman, Katherine, Farjoun, Yossi, Banks, Eric, Poterba, Timothy, Wang, Arcturus, Seed, Cotton, Whiffin, Nicola, Chong, Jessica X., Samocha, Kaitlin E., Pierce-Hoffman, Emma, Zappala, Zachary, O’Donnell-Luria, Anne H., Minikel, Eric Vallabh, Weisburd, Ben, Lek, Monkol, Ware, James S., Vittal, Christopher, Armean, Irina M., Bergelson, Louis, Cibulskis, Kristian, Connolly, Kristen M., Covarrubias, Miguel, Donnelly, Stacey, Ferriera, Steven, Gabriel, Stacey, Gentry, Jeff, Gupta, Namrata, Jeandet, Thibault, Kaplan, Diane, Llanwarne, Christopher, Munshi, Ruchi, Novod, Sam, Petrillo, Nikelle, Roazen, David, Ruano-Rubio, Valentin, Saltzman, Andrea, Schleicher, Molly, Soto, Jose, Tibbetts, Kathleen, Tolonen, Charlotte, Wade, Gordon, Talkowski, Michael E., Neale, Benjamin M., Daly, Mark J., and MacArthur, Daniel G.

Abstract

Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes1. Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.

Published
2020
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41. Ultra-rare disruptive and damaging mutations influence educational attainment in the general population

Author

Ganna, Andrea, primary, Genovese, Giulio, additional, Howrigan, Daniel P, additional, Byrnes, Andrea, additional, Kurki, Mitja I, additional, Zekavat, Seyedeh M, additional, Whelan, Christopher W, additional, Kals, Mart, additional, Nivard, Michel G, additional, Bloemendal, Alex, additional, Bloom, Jonathan M, additional, Goldstein, Jacqueline I, additional, Poterba, Timothy, additional, Seed, Cotton, additional, Handsaker, Robert E, additional, Natarajan, Pradeep, additional, Mägi, Reedik, additional, Gage, Diane, additional, Robinson, Elise B, additional, Metspalu, Andres, additional, Salomaa, Veikko, additional, Suvisaari, Jaana, additional, Purcell, Shaun M, additional, Sklar, Pamela, additional, Kathiresan, Sekar, additional, Daly, Mark J, additional, McCarroll, Steven A, additional, Sullivan, Patrick F, additional, Palotie, Aarno, additional, Esko, Tõnu, additional, Hultman, Christina M, additional, and Neale, Benjamin M, additional

Published
2016
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42. Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage.

Author

Marini, Sandro, Devan, William J., Radmanesh, Farid, Miyares, Laura, Poterba, Timothy, Hansen, Björn M., Norrving, Bo, Jimenez-Conde, Jordi, Giralt-Steinhauer, Eva, Elosua, Roberto, Cuadrado-Godia, Elisa, Soriano, Carolina, Roquer, Jaume, Kourkoulis, Christina E., Ayres, Alison M., Schwab, Kristin, Tirschwell, David L., Selim, Magdy, Brown, Devin L., and Silliman, Scott L.

Published
2018
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44. 17p12Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage

Author

Marini, Sandro, Devan, William J., Radmanesh, Farid, Miyares, Laura, Poterba, Timothy, Hansen, Björn M., Norrving, Bo, Jimenez-Conde, Jordi, Giralt-Steinhauer, Eva, Elosua, Roberto, Cuadrado-Godia, Elisa, Soriano, Carolina, Roquer, Jaume, Kourkoulis, Christina E., Ayres, Alison M., Schwab, Kristin, Tirschwell, David L., Selim, Magdy, Brown, Devin L., Silliman, Scott L., Worrall, Bradford B., Meschia, James F., Kidwell, Chelsea S., Montaner, Joan, Fernandez-Cadenas, Israel, Delgado, Pilar, Greenberg, Steven M., Lindgren, Arne, Matouk, Charles, Sheth, Kevin N., Woo, Daniel, Anderson, Christopher D., Rosand, Jonathan, and Falcone, Guido J.

Abstract

Supplemental Digital Content is available in the text.

Published
2018
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45. Addendum: The mutational constraint spectrum quantified from variation in 141,456 humans

Author

Gudmundsson, Sanna, Karczewski, Konrad J., Francioli, Laurent C., Tiao, Grace, Cummings, Beryl B., Alföldi, Jessica, Wang, Qingbo, Collins, Ryan L., Laricchia, Kristen M., Ganna, Andrea, Birnbaum, Daniel P., Gauthier, Laura D., Brand, Harrison, Solomonson, Matthew, Watts, Nicholas A., Rhodes, Daniel, Singer-Berk, Moriel, England, Eleina M., Seaby, Eleanor G., Kosmicki, Jack A., Walters, Raymond K., Tashman, Katherine, Farjoun, Yossi, Banks, Eric, Poterba, Timothy, Wang, Arcturus, Seed, Cotton, Whiffin, Nicola, Chong, Jessica X., Samocha, Kaitlin E., Pierce-Hoffman, Emma, Zappala, Zachary, O’Donnell-Luria, Anne H., Minikel, Eric Vallabh, Weisburd, Ben, Lek, Monkol, Ware, James S., Vittal, Christopher, Armean, Irina M., Bergelson, Louis, Cibulskis, Kristian, Connolly, Kristen M., Covarrubias, Miguel, Donnelly, Stacey, Ferriera, Steven, Gabriel, Stacey, Gentry, Jeff, Gupta, Namrata, Jeandet, Thibault, Kaplan, Diane, Llanwarne, Christopher, Munshi, Ruchi, Novod, Sam, Petrillo, Nikelle, Roazen, David, Ruano-Rubio, Valentin, Saltzman, Andrea, Schleicher, Molly, Soto, Jose, Tibbetts, Kathleen, Tolonen, Charlotte, Wade, Gordon, Talkowski, Michael E., Neale, Benjamin M., Daly, Mark J., and MacArthur, Daniel G.

Published
2021
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46. Ultra-rare disruptive and damaging mutations influence educational attainment in the general population

Author

Ganna, Andrea, Genovese, Giulio, Howrigan, Daniel P., Byrnes, Andrea, Kurki, Mitja, Zekavat, Seyedeh M., Whelan, Christopher W., Kals, Mart, Nivard, Michel G., Bloemendal, Alex, Bloom, Jonathan M., Goldstein, Jacqueline I., Poterba, Timothy, Seed, Cotton, Handsaker, Robert E., Natarajan, Pradeep, Mägi, Reedik, Gage, Diane, Robinson, Elise B., Metspalu, Andres, Salomaa, Veikko, Suvisaari, Jaana, Purcell, Shaun M., Sklar, Pamela, Kathiresan, Sekar, Daly, Mark J., McCarroll, Steven A., Sullivan, Patrick F., Palotie, Aarno, Esko, Tõnu, Hultman, Christina, and Neale, Benjamin M.

Abstract

Disruptive and damaging ultra-rare variants (URVs) in highly constrained (HC) genes are enriched in individuals with neurodevelopmental disorders. In the general population, this class of variants was associated with a decrease in years of education (YOE; −3.1 months; P-value=3.3×10−8). This effect was stronger among high brain-expressed genes and explained more YOE variance than pathogenic copy number variation, but less than common variants. Disruptive and damaging URVs in HC genes influence the determinants of YOE in the general population.

Published
2016
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47. A Genetic Investigation of Sex Bias in the Prevalence of Attention-Deficit/Hyperactivity Disorder

Author

Martin, Joanna, Walters, Raymond K., Demontis, Ditte, Mattheisen, Manuel, Lee, S. Hong, Robinson, Elise, Brikell, Isabell, Ghirardi, Laura, Larsson, Henrik, Lichtenstein, Paul, Eriksson, Nicholas, Werge, Thomas, Mortensen, Preben Bo, Pedersen, Marianne Giørtz, Mors, Ole, Nordentoft, Merete, Hougaard, David M., Bybjerg-Grauholm, Jonas, Wray, Naomi R., Franke, Barbara, Faraone, Stephen V., O’Donovan, Michael C., Thapar, Anita, Børglum, Anders D., Neale, Benjamin M., Agee, Michelle, Alipanahi, Babak, Auton, Adam, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Fontanillas, Pierre, Furlotte, Nicholas A., Hinds, David A., Hromatka, Bethann S., Huber, Karen E., Kleinman, Aaron, Litterman, Nadia K., McIntyre, Matthew H., Mountain, Joanna L., Northover, Carrie A.M., Pitts, Steven J., Sathirapongsasuti, J. Fah, Sazonova, Olga V., Shelton, Janie F., Shringarpure, Suyash, Tian, Chao, Tung, Joyce Y., Vacic, Vladimir, Wilson, Catherine H., Albayrak, Özgür, Anney, Richard J.L., Vasquez, Alejandro Arias, Arranz, Maria Jesús, Asherson, Philip, Banaschewski, Tobias, Banaschewski, Tobias J., Bau, Claiton, Biederman, Joseph, Børglum, Anders, Buitelaar, Jan K., Casas, Miguel, Charach, Alice, Cormand, Bru, Crosbie, Jennifer, Dalsgaard, Soeren, Daly, Mark J., Dempfle, Astrid, Doyle, Alysa E., Ebstein, Richard P., Elia, Josephine, Föcker, Manuel, Freitag, Christine, Gelernter, Joel, Gill, Michael, Grevet, Eugenio, Haavik, Jan, Hakonarson, Hakon, Hawi, Ziarih, Hebebrand, Johannes, Herpertz-Dahlmann, Beate, Hervas, Amaia, Hinney, Anke, Hohmann, Sarah, Holmans, Peter, Hutz, Mara, Ickowitz, Abel, Johansson, Stefan, Kent, Lindsey, Kittel-Schneider, Sarah, Kranzler, Henry, Kuntsi, Jonna, Lambregts-Rommelse, Nanda, Langley, Kate, Lehmkuhl, Gerd, Lesch, Klaus-Peter, Loo, Sandra K., McGough, James J., Medland, Sarah E., Meyer, Jobst, Mick, Eric, Middletion, Frank, Miranda, Ana, Mulas, Fernando, Mulligan, Aisling, Nelson, Stan F., Nguyen, T. Trang, Oades, Robert D., Owen, Michael J., Palmason, Haukur, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Renner, Tobias J., Rhode, Luis, Ribasés, Marta, Rietschel, Marcella, Ripke, Stephan, Rivero, Olga, Roeyers, Herbert, Romanos, Marcel, Romanos, Jasmin, Mota, Nina Roth, Rothenberger, Aribert, Sánchez-Mora, Cristina, Schachar, Russell, Schäfer, Helmut, Scherag, André, Schimmelmann, Benno G., Sergeant, Joseph, Sinzig, Judith, Smalley, Susan L., Sonuga-Barke, Edmund J.S., Steinhausen, Hans-Christoph, Sullivan, Patrick F., Thompsom, Margaret, Todorov, Alexandre, Waldman, Irwin, Walitza, Susanne, Walters, Raymond, Wang, Yufeng, Warnke, Andreas, Williams, Nigel, Witt, Stephanie H., Yang, Li, Zayats, Tetyana, Zhang-James, Yanli, Agerbo, Esben, Als, Thomas Damm, Bækved-Hansen, Marie, Belliveau, Rich, Cerrato, Felecia, Chambert, Kimberly, Churchhouse, Claire, Dalsgaard, Søren, Dumont, Ashley, Goldstein, Jacqueline, Grove, Jakob, Hansen, Christine S., Hauberg, Mads Engel, Hollegaard, Mads V., Howrigan, Daniel P., Huang, Hailiang, Maller, Julian, Martin, Alicia R., Moran, Jennifer, Pallesen, Jonatan, Palmer, Duncan S., Pedersen, Carsten Bøcker, Poterba, Timothy, Poulsen, Jesper Buchhave, Robinson, Elise B., Satterstrom, F. Kyle, Stevens, Christine, and Turley, Patrick

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48. Author Correction: Transcript expression-aware annotation improves rare variant interpretation.

Author

Cummings, Beryl B., Karczewski, Konrad J., Kosmicki, Jack A., Seaby, Eleanor G., Watts, Nicholas A., Singer-Berk, Moriel, Mudge, Jonathan M., Karjalainen, Juha, Satterstrom, F. Kyle, O'Donnell-Luria, Anne H., Poterba, Timothy, Seed, Cotton, Solomonson, Matthew, Alföldi, Jessica, Genome Aggregation Database Production Team, Armean, Irina M., Banks, Eric, Bergelson, Louis, Cibulskis, Kristian, and Collins, Ryan L.

Abstract

A Correction to this paper has been published: https://doi.org/10.1038/s41586-020-03175-7 [ABSTRACT FROM AUTHOR]

Published
2021
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49. Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders

Author

Arking, Dan E., Devlin, Bernie, Nørgaard-Pedersen, Bent, Nordentoft, Merete, Ercan-Sencicek, A. Gulhan, Amaral, David, Stefansson, Kari, Correia, Catarina T., Cantor, Rita M., Wijsman, Ellen M., Samocha, Kaitlin E., Anttila, Verneri, Duketis, Eftichia, Taylor, Jacob, Rogé, Bernadette, Hallmayer, Joachim, Børglum, Anders D, Hansen, Christine S., Regan, Regina, Pedersen, Carsten B., Conceição, Inês C., Geschwind, Daniel H., Bybjerg-Grauholm, Jonas, Reichenberg, Abraham, Buxbaum, Joseph D., Neale, Benjamin, Fallin, M. Daniele, Weiner, Daniel J., Ledbetter, David H., Anagnostou, Evdokia, Dumont, Ashley, Van Engeland, Herman, Silagadze, Teimuraz, Almeida, Joana, Santangelo, Susan, Sandin, Sven, Hansen, Christine, Rehnström, Karola, Bader, Joel S., Minshew, Nancy, Wittemeyer, Kerstin, Haines, Jonathan L., Vorstman, Jacob A. S., Bishop, Somer, Stevens, Christine, Magalhaes, Tiago, Hakonarson, Hakon, Guter, Stephen J., Skuse, David, Levitt, Pat, Poultney, Christopher S., Walters, Raymond K., Mortensen, Preben Bo, Magnusson, Pall, Grice, Dorothy E., Battaglia, Agatino, Willsey, A Jeremy, Green, Jonathan M., Svantesson, Oscar, Lord, Catherine, Piven, Joseph, Holmans, Peter, Bækvad-Hansen, Marie, Hultman, Christina M., Ladd-Acosta, Christine, Bourgeron, Thomas, DeRubeis, Silvia, Sutcliffe, James S., Robinson, Elise B., Nurnberger, John I., Baird, Gillian, Sanders, Stephan J, Mattheisen, Manuel, Rouleau, Guy A., Celestino-Soper, Patrícia B. S., Zwaigenbaum, Lonnie, Duque, Frederico, Ennis, Sean, Klei, Lambertus, Gill, Michael, McMahon, William M., Wigdor, Emilie M., McGrew, Susan G., Wallace, Simon, Roberts, Wendy, Casey, Jillian, Pejovic-Milovancevic, Milica, Iliadou, Bozenna, Soorya, Latha, Cook, Edwin H., Coon, Hilary, Stefansson, Hreinn, Cuccaro, Michael L., Paterson, Andrew D., Bölte, Sven, Bernier, Raphael, Merikangas, Alison, LeCouteur, Ann S., Poustka, Fritz, Parr, Jeremy R., Yu, Timothy W., Thompson, Ann P., Beaudet, Arthur L., Moran, Jennifer, Pagnamenta, Alistair T., Goldstein, Jacqueline I., DeLuca, Daniel Moreno, Daly, Mark J, Green, Andrew, Weiss, Lauren A., Palotie, Aarno, Folstein, Susan E., Roeder, Kathryn, Smith, George Davey, Jacob, Suma, Mors, Ole, Brennan, Sean, Grove, Jakob, Pinto, Dalila, Bal, Vanessa H., Huang, Hailiang, Waltes, Regina, Cafe, Cátia, Bailey, Anthony J., Delorme, Richard, Reichert, Jennifer, Leboyer, Marion, Walsh, Christopher A., Vicente, Astrid M., Goldberg, Arthur P., Dawson, Geraldine, DeJonge, Maretha V., Mouga, Susana, Hansen, Thomas F., Chiocchetti, Andreas G., Martin, Christa Lese, Scherer, Stephen W., Oliveira, Guiomar, Klauck, Sabine M., Bolton, Patrick F., Pedersen, Marianne G., Gilbert, John, Betancur, Catalina, Okbay, Aysu, Fombonne, Eric, Bolshakova, Nadia, Lowe, Jennifer K., Maestrini, Elena, Pericak-Vance, Margaret A., Martsenkovsky, Igor, Gallagher, Louise, Freitag, Christine M., Werge, Thomas, Vieland, Veronica J., State, Matthew W., Kolevzon, Alexander, Bacchelli, Elena, Poulsen, Jesper, Monaco, Anthony P., Anney, Richard, Howrigan, Daniel, Poterba, Timothy, Mane, Shrikant M., Hougaard, David M, Medland, Sarah E., Chakravarti, Aravinda, Hendren, Robert, Conroy, Judith, Tsang, Kathryn, Gillberg, Christopher, Steinberg, Stacy, Saemundsen, Evald, Fernandez, Bridget, Ripke, Stephan, Murtha, Michael T., Martin, Donna M., Morrow, Eric M., Kosmicki, Jack A., Schellenberg, Gerard D., Lee, Phil H., Wassink, Thomas H., Szatmari, Peter, and Hertz-Picciotto, Irva

Subjects
genetic structures, mental disorders, behavioral disciplines and activities, 3. Good health
Abstract

Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASDs and to identify subgroups of ASD cases, including those with strong acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test, and data from 6,454 families with a child with ASD, we show that polygenic risk for ASDs, schizophrenia, and greater educational attainment is over transmitted to children with ASDs. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strong acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that ASDs’ genetic influences are additive and suggest they create risk through at least partially distinct etiologic pathways.

50. Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome

Author

Sixto Garcia Minaur, Pankaj B. Agrawal, A. Micheil Innes, Catherine A. Brownstein, David S. Wargowski, Brenda McInnes, Isaac Wong, Albert E. Chudley, Jennifer E. Posey, Francesc López-Giráldez, Ping-Yee B Au, Alper Gezdirici, Kyrieckos A. Aleck, Eric Boerwinkle, Paolo Prontera, Bilgen Bilge Geçkinli, Yeting Zhang, An Nguyen, David A. Dyment, Jukka S. Moilanen, Alan H. Beggs, Nara Sobreira, Hatip Aydin, Elizabeth E. Blue, Kathryn Dunn, Gerald F. Cox, Bernard N. Chodirker, Harrison Brand, Jinchuan Xing, Hind Al Sharhan, Bert B.A. de Vries, Maria Juliana Rodovalho Doriqui, Davut Pehlivan, Shalini N. Jhangiani, Centers for Mendelian Genomics, Katrin Õunap, Cheryl R. Greenberg, Kaya Bilguvar, Carol L. Clericuzio, Cynthia J. Curry, Taila Hartley, Julie Lauzon, Michael J. Bamshad, Timothy Poterba, R. Brian Lowry, Jill A. Fahrner, Cullen M. Dutmer, M. E. Suzanne Lewis, Steve Buyske, Ender Karaca, Aziz Mhanni, William T. Gibson, Valentina Stanley, April Hall, Elke de Boer, Kristin D. Kernohan, Joseph G. Gleeson, P. Dane Witmer, Jungmin Choi, Danny Antaki, Małgorzata J.M. Nowaczyk, Sander Pajusalu, Anne H. O’Donnell-Luria, Sarah L. Sawyer, Zeynep Coban Akdemir, Tara C. Matise, Jennifer McEvoy-Venneri, Casie A. Genetti, Kym M. Boycott, Lynette S. Penney, Ada Hamosh, Eleina M. England, Deniz Torun, Maha S. Zaki, Deborah A. Nickerson, Dyment, David A., O'Donnell-Luria, Anne, Agrawal, Pankaj B., Coban Akdemir, Zeynep, Aleck, Kyrieckos A., Antaki, Danny, Al Sharhan, Hind, Au, Ping-Yee B., Aydin, Hatip, Beggs, Alan H., Bilguvar, Kaya, Boerwinkle, Eric, Brand, Harrison, Brownstein, Catherine A., Buyske, Steve, Chodirker, Bernard, Choi, Jungmin, Chudley, Albert E., Clericuzio, Carol L., Cox, Gerald F., Curry, Cynthia, de Boer, Elke, de Vries, Bert B. A., Dunn, Kathryn, Dutmer, Cullen M., England, Eleina M., Fahrner, Jill A., Geckinli, Bilgen B., Genetti, Casie A., Gezdirici, Alper, Gibson, William T., Gleeson, Joseph G., Greenberg, Cheryl R., Hall, April, Hamosh, Ada, Hartley, Taila, Jhangiani, Shalini N., Karaca, Ender, Kernohan, Kristin, Lauzon, Julie L., Lewis, M. E. Suzanne, Lowry, R. Brian, Lopez-Giraldez, Francesc, Matise, Tara C., McEvoy-Venneri, Jennifer, McInnes, Brenda, Mhanni, Aziz, Garcia Minaur, Sixto, Moilanen, Jukka, Nguyen, An, Nowaczyk, Malgorzata J. M., Posey, Jennifer E., Ounap, Katrin, Pehlivan, Davut, Pajusalu, Sander, Penney, Lynette S., Poterba, Timothy, Prontera, Paolo, Doriqui, Maria Juliana Rodovalho, Sawyer, Sarah L., Sobreira, Nara, Stanley, Valentina, Torun, Deniz, Wargowski, David, Witmer, P. Dane, Wong, Isaac, Xing, Jinchuan, Zaki, Maha S., Zhang, Yeting, Boycott, Kym M., Bamshad, Michael J., Nickerson, Deborah A., Blue, Elizabeth E., and Innes, A. Micheil

Subjects
0301 basic medicine, Male, ANOMALIES, INTELLECTUAL DISABILITY, Eczema, 030105 genetics & heredity, PHENOTYPE, genetic heterogeneity, Locus heterogeneity, Dubowitz syndrome, Exome, Child, Genetics (clinical), Exome sequencing, Growth Disorders, Genetics, FRAMESHIFT, Genomics, 3. Good health, VPS13B, genome sequencing, LOSS-OF-FUNCTION, Child, Preschool, symbols, Microcephaly, Female, microarray, Adolescent, DNA Copy Number Variations, Biology, NSUN2, PATIENT, DNA sequencing, Histone Deacetylases, Article, 03 medical and health sciences, symbols.namesake, medicine, Humans, Genetic Predisposition to Disease, ANEMIA, Genetic heterogeneity, Genome, Human, MUTATIONS, Facies, Infant, PLATFORM, medicine.disease, Repressor Proteins, 030104 developmental biology, Mendelian inheritance, exome sequencing
Abstract

Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a "Dubowitz-like" condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome-wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy-number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next-generation sequencing. Overall, the DubS-like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.

Published
2021

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