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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. Inferring compound heterozygosity from large-scale exome sequencing data

Author

Guo, Michael H., Francioli, Laurent C., Stenton, Sarah L., Goodrich, Julia K., Watts, Nicholas A., Singer-Berk, Moriel, Groopman, Emily, Darnowsky, Philip W., Solomonson, Matthew, Baxter, Samantha, Tiao, Grace, Neale, Benjamin M., Hirschhorn, Joel N., Rehm, Heidi L., Daly, Mark J., O’Donnell-Luria, Anne, Karczewski, Konrad J., MacArthur, Daniel G., and Samocha, Kaitlin E.

Published
2024
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3. 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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4. A structural variation reference for medical and population genetics

Author

Collins, Ryan L, Brand, Harrison, Karczewski, Konrad J, Zhao, Xuefang, Alföldi, Jessica, Francioli, Laurent C, Khera, Amit V, Lowther, Chelsea, Gauthier, Laura D, Wang, Harold, Watts, Nicholas A, Solomonson, Matthew, O’Donnell-Luria, Anne, Baumann, Alexander, Munshi, Ruchi, Walker, Mark, Whelan, Christopher W, Huang, Yongqing, Brookings, Ted, Sharpe, Ted, Stone, Matthew R, Valkanas, Elise, Fu, Jack, Tiao, Grace, Laricchia, Kristen M, Ruano-Rubio, Valentin, Stevens, Christine, Gupta, Namrata, Cusick, Caroline, Margolin, Lauren, Taylor, Kent D, Lin, Henry J, Rich, Stephen S, Post, Wendy S, Chen, Yii-Der Ida, Rotter, Jerome I, Nusbaum, Chad, Philippakis, Anthony, Lander, Eric, Gabriel, Stacey, Neale, Benjamin M, Kathiresan, Sekar, Daly, Mark J, Banks, Eric, MacArthur, Daniel G, and Talkowski, Michael E

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Biotechnology, Human Genome, Generic health relevance, Disease, Female, Genetic Testing, Genetic Variation, Genetics, Medical, Genetics, Population, Genome, Human, Genotyping Techniques, Humans, Male, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Racial Groups, Reference Standards, Selection, Genetic, Whole Genome Sequencing, Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, General Science & Technology
Abstract

Structural variants (SVs) rearrange large segments of DNA1 and can have profound consequences in evolution and human disease2,3. As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD)4 have become integral in the interpretation of single-nucleotide variants (SNVs)5. However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25-29% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage6. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9% of samples, and estimate that 0.13% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings7. This SV resource is freely distributed via the gnomAD browser8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening.

Published
2020

6. A high-quality human reference panel reveals the complexity and distribution of genomic structural variants.

Author

Hehir-Kwa, Jayne Y, Marschall, Tobias, Kloosterman, Wigard P, Francioli, Laurent C, Baaijens, Jasmijn A, Dijkstra, Louis J, Abdellaoui, Abdel, Koval, Vyacheslav, Thung, Djie Tjwan, Wardenaar, René, Renkens, Ivo, Coe, Bradley P, Deelen, Patrick, de Ligt, Joep, Lameijer, Eric-Wubbo, van Dijk, Freerk, Hormozdiari, Fereydoun, Genome of the Netherlands Consortium, Uitterlinden, André G, van Duijn, Cornelia M, Eichler, Evan E, de Bakker, Paul IW, Swertz, Morris A, Wijmenga, Cisca, van Ommen, Gert-Jan B, Slagboom, P Eline, Boomsma, Dorret I, Schönhuth, Alexander, Ye, Kai, and Guryev, Victor

Subjects
Genome of the Netherlands Consortium, Chromosomes, Humans, RNA, Polymerase Chain Reaction, Sequence Analysis, DNA, Sequence Analysis, RNA, Computational Biology, Genomics, Gene Deletion, Genotype, Haplotypes, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Genome, Human, Algorithms, Software, Netherlands, INDEL Mutation, Genomic Structural Variation, Sequence Analysis, DNA, Polymorphism, Single Nucleotide, Genome, Human
Abstract

Structural variation (SV) represents a major source of differences between individual human genomes and has been linked to disease phenotypes. However, the majority of studies provide neither a global view of the full spectrum of these variants nor integrate them into reference panels of genetic variation. Here, we analyse whole genome sequencing data of 769 individuals from 250 Dutch families, and provide a haplotype-resolved map of 1.9 million genome variants across 9 different variant classes, including novel forms of complex indels, and retrotransposition-mediated insertions of mobile elements and processed RNAs. A large proportion are previously under reported variants sized between 21 and 100 bp. We detect 4 megabases of novel sequence, encoding 11 new transcripts. Finally, we show 191 known, trait-associated SNPs to be in strong linkage disequilibrium with SVs and demonstrate that our panel facilitates accurate imputation of SVs in unrelated individuals.

Published
2016

7. Leveraging Distant Relatedness to Quantify Human Mutation and Gene-Conversion Rates

Author

Palamara, Pier Francesco, Francioli, Laurent C, Wilton, Peter R, Genovese, Giulio, Gusev, Alexander, Finucane, Hilary K, Sankararaman, Sriram, Consortium, Genome of the Netherlands, Sunyaev, Shamil R, de Bakker, Paul IW, Wakeley, John, Pe’er, Itsik, and Price, Alkes L

Subjects
Biological Sciences, Genetics, Biotechnology, Human Genome, Alleles, Gene Frequency, Genome, Human, Germ-Line Mutation, Haplotypes, Humans, INDEL Mutation, Linear Models, Models, Genetic, Mutation Rate, Recombination, Genetic, Genome of the Netherlands Consortium, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

The rate at which human genomes mutate is a central biological parameter that has many implications for our ability to understand demographic and evolutionary phenomena. We present a method for inferring mutation and gene-conversion rates by using the number of sequence differences observed in identical-by-descent (IBD) segments together with a reconstructed model of recent population-size history. This approach is robust to, and can quantify, the presence of substantial genotyping error, as validated in coalescent simulations. We applied the method to 498 trio-phased sequenced Dutch individuals and inferred a point mutation rate of 1.66 × 10(-8) per base per generation and a rate of 1.26 × 10(-9) for

Published
2015

8. 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, and Collins, Ryan L.

Subjects
Gene mutations -- Control -- Analysis, Gene silencing -- Analysis, Genetic variation -- Analysis, Human genome -- Identification and classification -- Analysis, Environmental issues, Science and technology, Zoology and wildlife conservation
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 sizes.sup.1. 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. A catalogue of predicted loss-of-function variants in 125,748 whole-exome and 15,708 whole-genome sequencing datasets from the Genome Aggregation Database (gnomAD) reveals the spectrum of mutational constraints that affect these human protein-coding genes., Author(s): Konrad J. Karczewski [sup.1] [sup.2] , Laurent C. Francioli [sup.1] [sup.2] , Grace Tiao [sup.1] [sup.2] , Beryl B. Cummings [sup.1] [sup.2] [sup.3] , Jessica Alföldi [sup.1] [sup.2] , [...]

Published
2020
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9. Characteristics of de novo structural changes in the human genome

Author

Kloosterman, Wigard P, Francioli, Laurent C, Hormozdiari, Fereydoun, Marschall, Tobias, Hehir-Kwa, Jayne Y, Abdellaoui, Abdel, Lameijer, Eric-Wubbo, Moed, Matthijs H, Koval, Vyacheslav, Renkens, Ivo, van Roosmalen, Markus J, Arp, Pascal, Karssen, Lennart C, Coe, Bradley P, Handsaker, Robert E, Suchiman, Eka D, Cuppen, Edwin, Thung, Djie Tjwan, McVey, Mitch, Wendl, Michael C, Consortium, Genome of the Netherlands, Uitterlinden, André, van Duijn, Cornelia M, Swertz, Morris A, Wijmenga, Cisca, van Ommen, GertJan B, Slagboom, P Eline, Boomsma, Dorret I, Schönhuth, Alexander, Eichler, Evan E, de Bakker, Paul IW, Ye, Kai, and Guryev, Victor

Subjects
Genetics, Human Genome, Alleles, Amino Acid Sequence, Female, Genetic Variation, Genome, Human, Genomics, Haplotypes, Humans, INDEL Mutation, Male, Molecular Sequence Data, Mutation Rate, Polymorphism, Single Nucleotide, Retroelements, Sequence Alignment, Sequence Analysis, DNA, Genome of Netherlands Consortium, Biological Sciences, Medical and Health Sciences, Bioinformatics
Abstract

Small insertions and deletions (indels) and large structural variations (SVs) are major contributors to human genetic diversity and disease. However, mutation rates and characteristics of de novo indels and SVs in the general population have remained largely unexplored. We report 332 validated de novo structural changes identified in whole genomes of 250 families, including complex indels, retrotransposon insertions, and interchromosomal events. These data indicate a mutation rate of 2.94 indels (1-20 bp) and 0.16 SVs (>20 bp) per generation. De novo structural changes affect on average 4.1 kbp of genomic sequence and 29 coding bases per generation, which is 91 and 52 times more nucleotides than de novo substitutions, respectively. This contrasts with the equal genomic footprint of inherited SVs and substitutions. An excess of structural changes originated on paternal haplotypes. Additionally, we observed a nonuniform distribution of de novo SVs across offspring. These results reveal the importance of different mutational mechanisms to changes in human genome structure across generations.

Published
2015

10. Genome of The Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels.

Author

van Leeuwen, Elisabeth M, Karssen, Lennart C, Deelen, Joris, Isaacs, Aaron, Medina-Gomez, Carolina, Mbarek, Hamdi, Kanterakis, Alexandros, Trompet, Stella, Postmus, Iris, Verweij, Niek, van Enckevort, David J, Huffman, Jennifer E, White, Charles C, Feitosa, Mary F, Bartz, Traci M, Manichaikul, Ani, Joshi, Peter K, Peloso, Gina M, Deelen, Patrick, van Dijk, Freerk, Willemsen, Gonneke, de Geus, Eco J, Milaneschi, Yuri, Penninx, Brenda WJH, Francioli, Laurent C, Menelaou, Androniki, Pulit, Sara L, Rivadeneira, Fernando, Hofman, Albert, Oostra, Ben A, Franco, Oscar H, Mateo Leach, Irene, Beekman, Marian, de Craen, Anton JM, Uh, Hae-Won, Trochet, Holly, Hocking, Lynne J, Porteous, David J, Sattar, Naveed, Packard, Chris J, Buckley, Brendan M, Brody, Jennifer A, Bis, Joshua C, Rotter, Jerome I, Mychaleckyj, Josyf C, Campbell, Harry, Duan, Qing, Lange, Leslie A, Wilson, James F, Hayward, Caroline, Polasek, Ozren, Vitart, Veronique, Rudan, Igor, Wright, Alan F, Rich, Stephen S, Psaty, Bruce M, Borecki, Ingrid B, Kearney, Patricia M, Stott, David J, Adrienne Cupples, L, Genome of The Netherlands Consortium, Jukema, J Wouter, van der Harst, Pim, Sijbrands, Eric J, Hottenga, Jouke-Jan, Uitterlinden, Andre G, Swertz, Morris A, van Ommen, Gert-Jan B, de Bakker, Paul IW, Eline Slagboom, P, Boomsma, Dorret I, Wijmenga, Cisca, and van Duijn, Cornelia M

Subjects
Genome of The Netherlands Consortium, Humans, Cholesterol, ATP-Binding Cassette Transporters, Gene Frequency, Mutation, Missense, Netherlands, Genetic Association Studies, Mutation, Missense
Abstract

Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of The Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value

Published
2015

11. A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy

Author

Kuiper, Jonas JW, Van Setten, Jessica, Ripke, Stephan, Van ‘T Slot, Ruben, Mulder, Flip, Missotten, Tom, Baarsma, G Seerp, Francioli, Laurent C, Pulit, Sara L, De Kovel, Carolien GF, Loon, Ninette Ten Dam-Van, Hollander, Anneke I Den, Veld, Paulien Huis in het, Hoyng, Carel B, Cordero-Coma, Miguel, Martín, Javier, Llorenç, Victor, Arya, Bharti, Thomas, Dhanes, Bakker, Steven C, Ophoff, Roel A, Rothova, Aniki, De Bakker, Paul IW, Mutis, Tuna, and Koeleman, Bobby PC

Subjects
Genetics, Prevention, Clinical Research, Autoimmune Disease, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Alleles, Aminopeptidases, Birdshot Chorioretinopathy, Case-Control Studies, Chorioretinitis, Female, Genome-Wide Association Study, HLA-A Antigens, Haplotypes, Humans, Male, Whites, White People, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Birdshot chorioretinopathy (BSCR) is a rare form of autoimmune uveitis that can lead to severe visual impairment. Intriguingly, >95% of cases carry the HLA-A29 allele, which defines the strongest documented HLA association for a human disease. We have conducted a genome-wide association study in 96 Dutch and 27 Spanish cases, and 398 unrelated Dutch and 380 Spanish controls. Fine-mapping the primary MHC association through high-resolution imputation at classical HLA loci, identified HLA-A*29:02 as the principal MHC association (odds ratio (OR) = 157.5, 95% CI 91.6-272.6, P = 6.6 × 10(-74)). We also identified two novel susceptibility loci at 5q15 near ERAP2 (rs7705093; OR = 2.3, 95% CI 1.7-3.1, for the T allele, P = 8.6 × 10(-8)) and at 14q32.31 in the TECPR2 gene (rs150571175; OR = 6.1, 95% CI 3.2-11.7, for the A allele, P = 3.2 × 10(-8)). The association near ERAP2 was confirmed in an independent British case-control samples (combined meta-analysis P = 1.7 × 10(-9)). Functional analyses revealed that the risk allele of the polymorphism near ERAP2 is strongly associated with high mRNA and protein expression of ERAP2 in B cells. This study further defined an extremely strong MHC risk component in BSCR, and detected evidence for a novel disease mechanism that affects peptide processing in the endoplasmic reticulum.

Published
2014

14. Inferring compound heterozygosity from large-scale exome sequencing data

Author

Guo, Michael H., Francioli, Laurent C., Stenton, Sarah L., Goodrich, Julia K., Watts, Nicholas A., Singer-Berk, Moriel, Groopman, Emily, Darnowsky, Philip W., Solomonson, Matthew, Baxter, Samantha, Tiao, Grace, Neale, Benjamin M., Hirschhorn, Joel N., Rehm, Heidi L., Daly, Mark J., O’Donnell-Luria, Anne, Karczewski, Konrad J., MacArthur, Daniel G., and Samocha, Kaitlin E.

Subjects
Article
Abstract

Severe recessive diseases arise when both the maternal and the paternal copies of a gene carry, or are impacted by, a damaging genetic variant in the affected individual. When a patient carries two different potentially causal variants, accurate diagnosis requires determining that these two variants occur on different copies of the chromosome (i.e., are in trans ) rather than on the same copy (i.e., in cis ). However, current approaches for determining phase, beyond parental testing, are limited in clinical settings. We developed a strategy for inferring phase for rare variant pairs within genes, leveraging haplotype patterns observed in exome sequencing data from the Genome Aggregation Database (gnomAD v2, n=125,748). When applied to trio data where phase is known, our approach estimates phase with high accuracy, even for very rare variants (frequency

Published
2023

15. Centers for Mendelian Genomics: A decade of facilitating gene discovery

Author

Baxter, Samantha M., primary, Posey, Jennifer E., additional, Lake, Nicole J., additional, Sobreira, Nara, additional, Chong, Jessica X., additional, Buyske, Steven, additional, Blue, Elizabeth E., additional, Chadwick, Lisa H., additional, Coban-Akdemir, Zeynep H., additional, Doheny, Kimberly F., additional, Davis, Colleen P., additional, Lek, Monkol, additional, Wellington, Christopher, additional, Jhangiani, Shalini N., additional, Gerstein, Mark, additional, Gibbs, Richard A., additional, Lifton, Richard P., additional, MacArthur, Daniel G., additional, Matise, Tara C., additional, Lupski, James R., additional, Valle, David, additional, Bamshad, Michael J., additional, Hamosh, Ada, additional, Mane, Shrikant, additional, Nickerson, Deborah A., additional, Rehm, Heidi L., additional, O’Donnell-Luria, Anne, additional, Adams, Marcia, additional, Aguet, François, additional, Akay, Gulsen, additional, Anderson, Peter, additional, Antonescu, Corina, additional, Arachchi, Harindra M., additional, Atik, Mehmed M., additional, Austin-Tse, Christina A., additional, Babb, Larry, additional, Bacus, Tamara J., additional, Bahrambeigi, Vahid, additional, Balasubramanian, Suganthi, additional, Bayram, Yavuz, additional, Beaudet, Arthur L., additional, Beck, Christine R., additional, Belmont, John W., additional, Below, Jennifer E., additional, Bilguvar, Kaya, additional, Boehm, Corinne D., additional, Boerwinkle, Eric, additional, Boone, Philip M., additional, Bowne, Sara J., additional, Brand, Harrison, additional, Buckingham, Kati J., additional, Byrne, Alicia B., additional, Calame, Daniel, additional, Campbell, Ian M., additional, Cao, Xiaolong, additional, Carvalho, Claudia, additional, Chander, Varuna, additional, Chang, Jaime, additional, Chao, Katherine R., additional, Chinn, Ivan K., additional, Clarke, Declan, additional, Collins, Ryan L., additional, Cummings, Beryl, additional, Dardas, Zain, additional, Dawood, Moez, additional, Delano, Kayla, additional, DiTroia, Stephanie P., additional, Doddapaneni, Harshavardhan, additional, Du, Haowei, additional, Du, Renqian, additional, Duan, Ruizhi, additional, Eldomery, Mohammad, additional, Eng, Christine M., additional, England, Eleina, additional, Evangelista, Emily, additional, Everett, Selin, additional, Fatih, Jawid, additional, Felsenfeld, Adam, additional, Francioli, Laurent C., additional, Frazar, Christian D., additional, Fu, Jack, additional, Gamarra, Emmanuel, additional, Gambin, Tomasz, additional, Gan, Weiniu, additional, Gandhi, Mira, additional, Ganesh, Vijay S., additional, Garimella, Kiran V., additional, Gauthier, Laura D., additional, Giroux, Danielle, additional, Gonzaga-Jauregui, Claudia, additional, Goodrich, Julia K., additional, Gordon, William W., additional, Griffith, Sean, additional, Grochowski, Christopher M., additional, Gu, Shen, additional, Gudmundsson, Sanna, additional, Hall, Stacey J., additional, Hansen, Adam, additional, Harel, Tamar, additional, Harmanci, Arif O., additional, Herman, Isabella, additional, Hetrick, Kurt, additional, Hijazi, Hadia, additional, Horike-Pyne, Martha, additional, Hsu, Elvin, additional, Hu, Jianhong, additional, Huang, Yongqing, additional, Hurless, Jameson R., additional, Jahl, Steve, additional, Jarvik, Gail P., additional, Jiang, Yunyun, additional, Johanson, Eric, additional, Jolly, Angad, additional, Karaca, Ender, additional, Khayat, Michael, additional, Knight, James, additional, Kolar, J. Thomas, additional, Kumar, Sushant, additional, Lalani, Seema, additional, Laricchia, Kristen M., additional, Larkin, Kathryn E., additional, Leal, Suzanne M., additional, Lemire, Gabrielle, additional, Lewis, Richard A., additional, Li, He, additional, Ling, Hua, additional, Lipson, Rachel B., additional, Liu, Pengfei, additional, Lovgren, Alysia Kern, additional, López-Giráldez, Francesc, additional, MacMillan, Melissa P., additional, Mangilog, Brian E., additional, Mano, Stacy, additional, Marafi, Dana, additional, Marosy, Beth, additional, Marshall, Jamie L., additional, Martin, Renan, additional, Marvin, Colby T., additional, Mawhinney, Michelle, additional, McGee, Sean, additional, McGoldrick, Daniel J., additional, Mehaffey, Michelle, additional, Mekonnen, Betselote, additional, Meng, Xiaolu, additional, Mitani, Tadahiro, additional, Miyake, Christina Y., additional, Mohr, David, additional, Morris, Shaine, additional, Mullen, Thomas E., additional, Murdock, David R., additional, Murugan, Mullai, additional, Muzny, Donna M., additional, Myers, Ben, additional, Neira, Juanita, additional, Nguyen, Kevin K., additional, Nielsen, Patrick M., additional, Nudelman, Natalie, additional, O’Heir, Emily, additional, O’Leary, Melanie C., additional, Ongaco, Chrissie, additional, Orange, Jordan, additional, Osei-Owusu, Ikeoluwa A., additional, Paine, Ingrid S., additional, Pais, Lynn S., additional, Paschall, Justin, additional, Patterson, Karynne, additional, Pehlivan, Davut, additional, Pelle, Benjamin, additional, Penney, Samantha, additional, Perez de Acha Chavez, Jorge, additional, Pierce-Hoffman, Emma, additional, Poli, Cecilia M., additional, Punetha, Jaya, additional, Radhakrishnan, Aparna, additional, Richardson, Matthew A., additional, Rodrigues, Eliete, additional, Roote, Gwendolin T., additional, Rosenfeld, Jill A., additional, Ryke, Erica L., additional, Sabo, Aniko, additional, Sanchez, Alice, additional, Schrauwen, Isabelle, additional, Scott, Daryl A., additional, Sedlazeck, Fritz, additional, Serrano, Jillian, additional, Shaw, Chad A., additional, Shelford, Tameka, additional, Shively, Kathryn M., additional, Singer-Berk, Moriel, additional, Smith, Joshua D., additional, Snow, Hana, additional, Snyder, Grace, additional, Solomonson, Matthew, additional, Son, Rachel G., additional, Song, Xiaofei, additional, Stankiewicz, Pawel, additional, Stephan, Taylorlyn, additional, Sutton, V. Reid, additional, Sveden, Abigail, additional, Sánchez, Diana Cornejo, additional, Tackett, Monica, additional, Talkowski, Michael, additional, Threlkeld, Machiko S., additional, Tiao, Grace, additional, Udler, Miriam S., additional, Vail, Laura, additional, Valivullah, Zaheer, additional, Valkanas, Elise, additional, VanNoy, Grace E., additional, Wang, Qingbo S., additional, Wang, Gao, additional, Wang, Lu, additional, Wangler, Michael F., additional, Watts, Nicholas A., additional, Weisburd, Ben, additional, Weiss, Jeffrey M., additional, Wheeler, Marsha M., additional, White, Janson J., additional, Williamson, Clara E., additional, Wilson, Michael W., additional, Wiszniewski, Wojciech, additional, Withers, Marjorie A., additional, Witmer, Dane, additional, Witzgall, Lauren, additional, Wohler, Elizabeth, additional, Wojcik, Monica H., additional, Wong, Isaac, additional, Wood, Jordan C., additional, Wu, Nan, additional, Xing, Jinchuan, additional, Yang, Yaping, additional, Yi, Qian, additional, Yuan, Bo, additional, Zeiger, Jordan E., additional, Zhang, Chaofan, additional, Zhang, Peng, additional, Zhang, Yan, additional, Zhang, Xiaohong, additional, Zhang, Yeting, additional, Zhang, Shifa, additional, Zoghbi, Huda, additional, and van den Veyver, Igna, additional

Published
2022
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16. 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

17. Author Correction: A structural variation reference for medical and population genetics

Author

Collins, Ryan L., Brand, Harrison, Karczewski, Konrad J., Zhao, Xuefang, Alföldi, Jessica, Francioli, Laurent C., and Khera, Amit V.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

A Correction to this paper has been published: https://doi.org/10.1038/s41586-020-03176-6., Author(s): Ryan L. Collins [sup.1] [sup.2] [sup.3] , Harrison Brand [sup.1] [sup.2] [sup.4] , Konrad J. Karczewski [sup.1] [sup.5] , Xuefang Zhao [sup.1] [sup.2] [sup.4] , Jessica Alföldi [sup.1] [sup.5] [...]

Published
2021
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19. 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

20. An open resource of structural variation for medical and population genetics

Author

Collins, Ryan L., Brand, Harrison, Karczewski, Konrad J., Zhao, Xuefang, Alföldi, Jessica, Francioli, Laurent C., Khera, Amit V., Lowther, Chelsea, Gauthier, Laura D., Wang, Harold, Watts, Nicholas A., Solomonson, Matthew, O’Donnell-Luria, Anne, Baumann, Alexander, Munshi, Ruchi, Walker, Mark, Whelan, Christopher, Huang, Yongqing, Brookings, Ted, Sharpe, Ted, Stone, Matthew R., Valkanas, Elise, Fu, Jack, Tiao, Grace, Laricchia, Kristen M., Ruano-Rubio, Valentin, Stevens, Christine, Gupta, Namrata, Margolin, Lauren, Taylor, Kent D., Lin, Henry J., Rich, Stephen S., Post, Wendy, Chen, Yii-Der Ida, Rotter, Jerome I., Nusbaum, Chad, Philippakis, Anthony, Lander, Eric, Gabriel, Stacey, Neale, Benjamin M., Kathiresan, Sekar, Daly, Mark J., Banks, Eric, MacArthur, Daniel G., and Talkowski, Michael E.

Subjects
Structural variation, 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Resource (biology), business.industry, Environmental resource management, Population genetics, Biology, business, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

SUMMARYStructural variants (SVs) rearrange large segments of the genome and can have profound consequences for evolution and human diseases. As national biobanks, disease association studies, and clinical genetic testing grow increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD) have become integral for interpreting genetic variation. To date, no large-scale reference maps of SVs exist from high-coverage sequencing comparable to those available for point mutations in protein-coding genes. Here, we constructed a reference atlas of SVs across 14,891 genomes from diverse global populations (54% non-European) as a component of gnomAD. We discovered a rich landscape of 433,371 distinct SVs, including 5,295 multi-breakpoint complex SVs across 11 mutational subclasses, and examples of localized chromosome shattering, as in chromothripsis. The average individual harbored 7,439 SVs, which accounted for 25-29% of all rare protein-truncating events per genome. We found strong correlations between constraint against damaging point mutations and rare SVs that both disrupt and duplicate protein-coding sequence, suggesting intolerance to reciprocal dosage alterations for a subset of tightly regulated genes. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than any effect on noncoding SVs. Finally, we benchmarked carrier rates for medically relevant SVs, finding very large (≥1Mb) rare SVs in 3.8% of genomes (~1:26 individuals) and clinically reportable incidental SVs in 0.18% of genomes (~1:556 individuals). These data have been integrated directly into the gnomAD browser (https://gnomad.broadinstitute.org) and will have broad utility for population genetics, disease association, and diagnostic screening.

Published
2019
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21. 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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22. 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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23. Integrated clinical and omics approach to rare diseases : Novel genes and oligogenic inheritance in holoprosencephaly

Author

Kim, Artem, Savary, Clara, Dubourg, Christèle, Carré, Wilfrid, Mouden, Charlotte, Hamdi-Rozé, Houda, Guyodo, Hélène, Douce, Jerome Le, Génin, Emmanuelle, Campion, Dominique, Dartigues, Jean François, Deleuze, Jean François, Lambert, Jean Charles, Redon, Richard, Ludwig, Thomas, Grenier-Boley, Benjamin, Letort, Sébastien, Lindenbaum, Pierre, Meyer, Vincent, Quenez, Olivier, Dina, Christian, Bellenguez, Céline, Charbonnier-Le Clézio, Camille, Giemza, Joanna, Chatel, Stéphanie, Férec, Claude, Le Marec, Hervé, Letenneur, Luc, Nicolas, Gaël, Rouault, Karen, Bacq, Delphine, Boland, Anne, Lechner, Doris, Wijmenga, Cisca, Swertz, Morris A., Eline Slagboom, P., Van Ommen, Gert Jan B., Van Duijn, Cornelia M., Boomsma, Dorret I., De Bakker, Paul I.W., Bovenberg, Jasper A., De Craen, Anton J.M., Beekman, Marian, Hofman, Albert, Willemsen, Gonneke, Wolffenbuttel, Bruce, Platteel, Mathieu, Du, Yuanping, Chen, Ruoyan, Cao, Hongzhi, Cao, Rui, Sun, Yushen, Sujie Cao, Jeremy, Van Dijk, Freerk, Neerincx, Pieter B.T., Deelen, Patrick, Dijkstra, Martijn, Byelas, George, Kanterakis, Alexandros, Bot, Jan, Ye, Kai, Lameijer, Eric Wubbo, Vermaat, Martijn, Laros, Jeroen F.J., Den Dunnen, Johan T., De Knijff, Peter, Karssen, Lennart C., Van Leeuwen, Elisa M., Amin, Najaf, Koval, Vyacheslav, Rivadeneira, Fernando, Estrada, Karol, Hehir-Kwa, Jayne Y., De Ligt, Joep, Abdellaoui, Abdel, Hottenga, Jouke Jan, Mathijs Kattenberg, V., Van Enckevort, David, Mei, Hailiang, Santcroos, Mark, Van Schaik, Barbera D.C., Handsaker, Robert E., McCarroll, Steven A., Eichler, Evan E., Ko, Arthur, Sudmant, Peter, Francioli, Laurent C., Kloosterman, Wigard P., Nijman, Isaac J., Guryev, Victor, Pasquier, Laurent, Flori, Elisabeth, Gonzales, Marie, Bénéteau, Claire, Boute, Odile, Attié-Bitach, Tania, Roume, Joelle, Goujon, Louise, Akloul, Linda, Odent, Sylvie, Watrin, Erwan, Dupé, Valérie, De Tayrac, Marie, David, Véronique, Kim, Artem, Savary, Clara, Dubourg, Christèle, Carré, Wilfrid, Mouden, Charlotte, Hamdi-Rozé, Houda, Guyodo, Hélène, Douce, Jerome Le, Génin, Emmanuelle, Campion, Dominique, Dartigues, Jean François, Deleuze, Jean François, Lambert, Jean Charles, Redon, Richard, Ludwig, Thomas, Grenier-Boley, Benjamin, Letort, Sébastien, Lindenbaum, Pierre, Meyer, Vincent, Quenez, Olivier, Dina, Christian, Bellenguez, Céline, Charbonnier-Le Clézio, Camille, Giemza, Joanna, Chatel, Stéphanie, Férec, Claude, Le Marec, Hervé, Letenneur, Luc, Nicolas, Gaël, Rouault, Karen, Bacq, Delphine, Boland, Anne, Lechner, Doris, Wijmenga, Cisca, Swertz, Morris A., Eline Slagboom, P., Van Ommen, Gert Jan B., Van Duijn, Cornelia M., Boomsma, Dorret I., De Bakker, Paul I.W., Bovenberg, Jasper A., De Craen, Anton J.M., Beekman, Marian, Hofman, Albert, Willemsen, Gonneke, Wolffenbuttel, Bruce, Platteel, Mathieu, Du, Yuanping, Chen, Ruoyan, Cao, Hongzhi, Cao, Rui, Sun, Yushen, Sujie Cao, Jeremy, Van Dijk, Freerk, Neerincx, Pieter B.T., Deelen, Patrick, Dijkstra, Martijn, Byelas, George, Kanterakis, Alexandros, Bot, Jan, Ye, Kai, Lameijer, Eric Wubbo, Vermaat, Martijn, Laros, Jeroen F.J., Den Dunnen, Johan T., De Knijff, Peter, Karssen, Lennart C., Van Leeuwen, Elisa M., Amin, Najaf, Koval, Vyacheslav, Rivadeneira, Fernando, Estrada, Karol, Hehir-Kwa, Jayne Y., De Ligt, Joep, Abdellaoui, Abdel, Hottenga, Jouke Jan, Mathijs Kattenberg, V., Van Enckevort, David, Mei, Hailiang, Santcroos, Mark, Van Schaik, Barbera D.C., Handsaker, Robert E., McCarroll, Steven A., Eichler, Evan E., Ko, Arthur, Sudmant, Peter, Francioli, Laurent C., Kloosterman, Wigard P., Nijman, Isaac J., Guryev, Victor, Pasquier, Laurent, Flori, Elisabeth, Gonzales, Marie, Bénéteau, Claire, Boute, Odile, Attié-Bitach, Tania, Roume, Joelle, Goujon, Louise, Akloul, Linda, Odent, Sylvie, Watrin, Erwan, Dupé, Valérie, De Tayrac, Marie, and David, Véronique

Published
2019

24. Integrated clinical and omics approach to rare diseases: Novel genes and oligogenic inheritance in holoprosencephaly

Author

CMM Groep Kaaij, Genetica Klinische Genetica, Cancer, CMM Groep De Ridder, Child Health, CMM Groep Kloosterman, CMM USEQ Facility, Hubrecht Institute with UMC, Kim, Artem, Savary, Clara, Dubourg, Christèle, Carré, Wilfrid, Mouden, Charlotte, Hamdi-Rozé, Houda, Guyodo, Hélène, Douce, Jerome Le, Génin, Emmanuelle, Campion, Dominique, Dartigues, Jean François, Deleuze, Jean François, Lambert, Jean Charles, Redon, Richard, Ludwig, Thomas, Grenier-Boley, Benjamin, Letort, Sébastien, Lindenbaum, Pierre, Meyer, Vincent, Quenez, Olivier, Dina, Christian, Bellenguez, Céline, Charbonnier-Le Clézio, Camille, Giemza, Joanna, Chatel, Stéphanie, Férec, Claude, Le Marec, Hervé, Letenneur, Luc, Nicolas, Gaël, Rouault, Karen, Bacq, Delphine, Boland, Anne, Lechner, Doris, Wijmenga, Cisca, Swertz, Morris A., Eline Slagboom, P., Van Ommen, Gert Jan B., Van Duijn, Cornelia M., Boomsma, Dorret I., De Bakker, Paul I.W., Bovenberg, Jasper A., De Craen, Anton J.M., Beekman, Marian, Hofman, Albert, Willemsen, Gonneke, Wolffenbuttel, Bruce, Platteel, Mathieu, Du, Yuanping, Chen, Ruoyan, Cao, Hongzhi, Cao, Rui, Sun, Yushen, Sujie Cao, Jeremy, Van Dijk, Freerk, Neerincx, Pieter B.T., Deelen, Patrick, Dijkstra, Martijn, Byelas, George, Kanterakis, Alexandros, Bot, Jan, Ye, Kai, Lameijer, Eric Wubbo, Vermaat, Martijn, Laros, Jeroen F.J., Den Dunnen, Johan T., De Knijff, Peter, Karssen, Lennart C., Van Leeuwen, Elisa M., Amin, Najaf, Koval, Vyacheslav, Rivadeneira, Fernando, Estrada, Karol, Hehir-Kwa, Jayne Y., De Ligt, Joep, Abdellaoui, Abdel, Hottenga, Jouke Jan, Mathijs Kattenberg, V., Van Enckevort, David, Mei, Hailiang, Santcroos, Mark, Van Schaik, Barbera D.C., Handsaker, Robert E., McCarroll, Steven A., Eichler, Evan E., Ko, Arthur, Sudmant, Peter, Francioli, Laurent C., Kloosterman, Wigard P., Nijman, Isaac J., Guryev, Victor, Pasquier, Laurent, Flori, Elisabeth, Gonzales, Marie, Bénéteau, Claire, Boute, Odile, Attié-Bitach, Tania, Roume, Joelle, Goujon, Louise, Akloul, Linda, Odent, Sylvie, Watrin, Erwan, Dupé, Valérie, De Tayrac, Marie, David, Véronique, CMM Groep Kaaij, Genetica Klinische Genetica, Cancer, CMM Groep De Ridder, Child Health, CMM Groep Kloosterman, CMM USEQ Facility, Hubrecht Institute with UMC, Kim, Artem, Savary, Clara, Dubourg, Christèle, Carré, Wilfrid, Mouden, Charlotte, Hamdi-Rozé, Houda, Guyodo, Hélène, Douce, Jerome Le, Génin, Emmanuelle, Campion, Dominique, Dartigues, Jean François, Deleuze, Jean François, Lambert, Jean Charles, Redon, Richard, Ludwig, Thomas, Grenier-Boley, Benjamin, Letort, Sébastien, Lindenbaum, Pierre, Meyer, Vincent, Quenez, Olivier, Dina, Christian, Bellenguez, Céline, Charbonnier-Le Clézio, Camille, Giemza, Joanna, Chatel, Stéphanie, Férec, Claude, Le Marec, Hervé, Letenneur, Luc, Nicolas, Gaël, Rouault, Karen, Bacq, Delphine, Boland, Anne, Lechner, Doris, Wijmenga, Cisca, Swertz, Morris A., Eline Slagboom, P., Van Ommen, Gert Jan B., Van Duijn, Cornelia M., Boomsma, Dorret I., De Bakker, Paul I.W., Bovenberg, Jasper A., De Craen, Anton J.M., Beekman, Marian, Hofman, Albert, Willemsen, Gonneke, Wolffenbuttel, Bruce, Platteel, Mathieu, Du, Yuanping, Chen, Ruoyan, Cao, Hongzhi, Cao, Rui, Sun, Yushen, Sujie Cao, Jeremy, Van Dijk, Freerk, Neerincx, Pieter B.T., Deelen, Patrick, Dijkstra, Martijn, Byelas, George, Kanterakis, Alexandros, Bot, Jan, Ye, Kai, Lameijer, Eric Wubbo, Vermaat, Martijn, Laros, Jeroen F.J., Den Dunnen, Johan T., De Knijff, Peter, Karssen, Lennart C., Van Leeuwen, Elisa M., Amin, Najaf, Koval, Vyacheslav, Rivadeneira, Fernando, Estrada, Karol, Hehir-Kwa, Jayne Y., De Ligt, Joep, Abdellaoui, Abdel, Hottenga, Jouke Jan, Mathijs Kattenberg, V., Van Enckevort, David, Mei, Hailiang, Santcroos, Mark, Van Schaik, Barbera D.C., Handsaker, Robert E., McCarroll, Steven A., Eichler, Evan E., Ko, Arthur, Sudmant, Peter, Francioli, Laurent C., Kloosterman, Wigard P., Nijman, Isaac J., Guryev, Victor, Pasquier, Laurent, Flori, Elisabeth, Gonzales, Marie, Bénéteau, Claire, Boute, Odile, Attié-Bitach, Tania, Roume, Joelle, Goujon, Louise, Akloul, Linda, Odent, Sylvie, Watrin, Erwan, Dupé, Valérie, De Tayrac, Marie, and David, Véronique

Published
2019

25. WGS-based telomere length analysis in Dutch family trios implicates stronger maternal inheritance and a role for RRM1 gene

Author

Nersisyan, Lilit, Nikoghosyan, Maria, Francioli, Laurent C., Menelaou, Androniki, Pulit, Sara L., Elbers, Clara C., Kloosterman, Wigard P., van Setten, Jessica, Nijman, Isaac J., Renkens, Ivo, de Bakker, Paul I. W., van Dijk, Freerk, Neerincx, Pieter B. T., Deelen, Patrick, Kanterakis, Alexandros, Dijkstra, Martijn, Byelas, Heorhiy, van der Velde, K. Joeri, Platteel, Mathieu, Swertz, Morris A., Wijmenga, Cisca, Palamara, Pier Francesco, Pe'er, Itsik, Ye, Kai, Lameijer, Eric-Wubbo, Moed, Matthijs H., Beekman, Marian, de Craen, Anton J. M., Suchiman, H. Eka D., Slagboom, P. Eline, Guryev, Victor, Abdellaoui, Abdel, Hottenga, Jouke Jan, Kattenberg, Mathijs, Willemsen, Gonneke, Boomsma, Dorret I., van Leeuwen, Elisabeth M., Karssen, Lennart C., Amin, Najaf, Rivadeneira, Fernando, Isaacs, Aaron, Hofman, Albert, Uitterlinden, Andre G., van Duijn, Cornelia M., van Oven, Mannis, Kayser, Manfred, Vermaat, Martijn, Laros, Jeroen F. J., den Dunnen, Johan T., van Enckevort, David, Mei, Hailiang, Li, Mingkun, Stoneking, Mark, van Schaik, Barbera D. C., Bot, Jan, Marschall, Tobias, Schonhuth, Alexander, Hehir-Kwa, Jayne Y., Handsaker, Robert E., Polak, Paz, Sohail, Mashaal, Vuzman, Dana, Estrada, Karol, McCarroll, Steven A., Sunyaev, Shamil R., Hormozdiari, Fereydoun, Koval, Vyacheslav, Medina-Gomez, Carolina, Oostra, Ben, Veldink, Jan H., van den Berg, Leonard H., Pitts, Steven J., Potluri, Shobha, Sundar, Purnima, Cox, David R., de Knijff, Peter, Li, Qibin, Li, Yingrui, Du, Yuanping, Chen, Ruoyan, Cao, Hongzhi, Wang, Jun, Li, Ning, Cao, Sujie, Bovenberg, Jasper A., van Ommen, Gert-Jan B., Arakelyan, Arsen, Nersisyan, Lilit, Nikoghosyan, Maria, Francioli, Laurent C., Menelaou, Androniki, Pulit, Sara L., Elbers, Clara C., Kloosterman, Wigard P., van Setten, Jessica, Nijman, Isaac J., Renkens, Ivo, de Bakker, Paul I. W., van Dijk, Freerk, Neerincx, Pieter B. T., Deelen, Patrick, Kanterakis, Alexandros, Dijkstra, Martijn, Byelas, Heorhiy, van der Velde, K. Joeri, Platteel, Mathieu, Swertz, Morris A., Wijmenga, Cisca, Palamara, Pier Francesco, Pe'er, Itsik, Ye, Kai, Lameijer, Eric-Wubbo, Moed, Matthijs H., Beekman, Marian, de Craen, Anton J. M., Suchiman, H. Eka D., Slagboom, P. Eline, Guryev, Victor, Abdellaoui, Abdel, Hottenga, Jouke Jan, Kattenberg, Mathijs, Willemsen, Gonneke, Boomsma, Dorret I., van Leeuwen, Elisabeth M., Karssen, Lennart C., Amin, Najaf, Rivadeneira, Fernando, Isaacs, Aaron, Hofman, Albert, Uitterlinden, Andre G., van Duijn, Cornelia M., van Oven, Mannis, Kayser, Manfred, Vermaat, Martijn, Laros, Jeroen F. J., den Dunnen, Johan T., van Enckevort, David, Mei, Hailiang, Li, Mingkun, Stoneking, Mark, van Schaik, Barbera D. C., Bot, Jan, Marschall, Tobias, Schonhuth, Alexander, Hehir-Kwa, Jayne Y., Handsaker, Robert E., Polak, Paz, Sohail, Mashaal, Vuzman, Dana, Estrada, Karol, McCarroll, Steven A., Sunyaev, Shamil R., Hormozdiari, Fereydoun, Koval, Vyacheslav, Medina-Gomez, Carolina, Oostra, Ben, Veldink, Jan H., van den Berg, Leonard H., Pitts, Steven J., Potluri, Shobha, Sundar, Purnima, Cox, David R., de Knijff, Peter, Li, Qibin, Li, Yingrui, Du, Yuanping, Chen, Ruoyan, Cao, Hongzhi, Wang, Jun, Li, Ning, Cao, Sujie, Bovenberg, Jasper A., van Ommen, Gert-Jan B., and Arakelyan, Arsen

Published
2019

26. Transmission of human mtDNA heteroplasmy in the Genome of the Netherlands families: support for a variable-size bottleneck

Author

Li, Mingkun, Rothwell, Rebecca, Vermaat, Martijn, Wachsmuth, Manja, Schröder, Roland, Laros, Jeroen F J, Van Oven, Mannis, De Bakker, Paul I W, Bovenberg, Jasper A., Van Duijn, Cornelia M., Van Ommen, Gert Jan B, Slagboom, P. Eline, Swertz, Morris A., Wijmenga, Cisca, Kayser, Manfred, Boomsma, Dorret I., Zöllner, Sebastian, De Knijff, Peter, Stoneking, Mark, De Craen, Anton J M, Beekman, Marian, Hofman, Albert, Willemsen, Gonneke, Wolffenbuttel, Bruce, Platteel, Mathieu, Du, Yuanping, Chen, Ruoyan, Cao, Hongzhi, Cao, Rui, Sun, Yushen, Cao, Jeremy Sujie, Van Dijk, Freerk, Neerincx, Pieter B T, Deelen, Patrick, Dijkstra, Martijn, Byelas, George, Kanterakis, Alexandros, Bot, Jan, Ye, Kai, Lameijer, Eric Wubbo, Den Dunnen, Johan T., Karssen, Lennart C., Van Leeuwen, Elisa M., Amin, Najaf, Koval, Vyacheslav, Rivadeneira, Fernando, Estrada, Karol, Hehir-Kwa, Jayne Y., De Ligt, Joep, Abdellaoui, Abdel, Hottenga, Jouke Jan, Kattenberg, V. Mathijs, Van Enckevort, David, Mei, Hailiang, Santcroos, Mark, Van Schaik, Barbera D C, Handsaker, Robert E., McCarroll, Steven A., Eichler, Evan E., Ko, Arthur, Sudmant, Peter, Francioli, Laurent C., Kloosterman, Wigard P., Nijman, Isaac J., Guryev, Victor, Genetic Identification, Epidemiology, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Biological Psychology, EMGO+ - Quality of Care, and Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep

Subjects
Male, Netherlands Twin Register (NTR), 0301 basic medicine, LEVEL, Inheritance Patterns, Twins, Twin Study, POINT MUTATIONS, Genome, Gene Frequency, Paternal mtDNA transmission, Genetics(clinical), Non-U.S. Gov't, Genetics (clinical), Netherlands, Genetics, Research Support, Non-U.S. Gov't, PURIFYING SELECTION, MITOCHONDRIAL-DNA MUTATIONS, RANDOM GENETIC DRIFT, HUMAN-DISEASE, Heteroplasmy, Female, Mitochondrial DNA, TISSUES, OOCYTES, Biology, Research Support, INHERITANCE, DNA, Mitochondrial, White People, Genetic Heterogeneity, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Journal Article, Humans, Family, Selection, Genetic, Allele, Allele frequency, Alleles, Models, Statistical, Polymorphism, Genetic, Models, Genetic, Research, Twin study, Minor allele frequency, 030104 developmental biology, Mutation, MELAS SYNDROME
Abstract

Although previous studies have documented a bottleneck in the transmission of mtDNA genomes from mothers to offspring, several aspects remain unclear, including the size and nature of the bottleneck. Here, we analyze the dynamics of mtDNA heteroplasmy transmission in the Genomes of the Netherlands (GoNL) data, which consists of complete mtDNA genome sequences from 228 trios, eight dizygotic (DZ) twin quartets, and 10 monozygotic (MZ) twin quartets. Using a minor allele frequency (MAF) threshold of 2%, we identified 189 heteroplasmies in the trio mothers, of which 59% were transmitted to offspring, and 159 heteroplasmies in the trio offspring, of which 70% were inherited from the mothers. MZ twin pairs exhibited greater similarity in MAF at heteroplasmic sites than DZ twin pairs, suggesting that the heteroplasmy MAF in the oocyte is the major determinant of the heteroplasmy MAF in the offspring. We used a likelihood method to estimate the effective number of mtDNA genomes transmitted to offspring under different bottleneck models; a variable bottleneck size model provided the best fit to the data, with an estimated mean of nine individual mtDNA genomes transmitted. We also found evidence for negative selection during transmission against novel heteroplasmies (in which the minor allele has never been observed in polymorphism data). These novel heteroplasmies are enhanced for tRNA and rRNA genes, and mutations associated with mtDNA diseases frequently occur in these genes. Our results thus suggest that the female germ line is able to recognize and select against deleterious heteroplasmies.

Published
2016
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27. Characterising the loss-of-function impact of 5' untranslated region variants in 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., Genome Aggregation Database Production Team, Armean, Irina M., Banks, Eric, Bergelson, Louis, Cibulskis, Kristian, Collins, Ryan L., and Connolly, Kristen M.

Subjects
GENETIC translation, NUCLEOTIDE sequencing, GENETIC code, GENOMES, EXOMES
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. [ABSTRACT FROM AUTHOR]

Published
2020
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28. Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes.

Author

Wang, Qingbo, Pierce-Hoffman, Emma, Cummings, Beryl B., Alföldi, Jessica, Francioli, Laurent C., Gauthier, Laura D., Hill, Andrew J., O'Donnell-Luria, Anne H., Genome Aggregation Database Production Team, Armean, Irina M., Banks, Eric, Bergelson, Louis, Cibulskis, Kristian, Collins, Ryan L., Connolly, Kristen M., Covarrubias, Miguel, Daly, Mark J., Donnelly, Stacey, Farjoun, Yossi, and Ferriera, Steven

Subjects
AMINO acid sequence, GENOMES, DEAMINATION, EXOMES
Abstract

Multi-nucleotide variants (MNVs), defined as two or more nearby variants existing on the same haplotype in an individual, are a clinically and biologically important class of genetic variation. However, existing tools typically do not accurately classify MNVs, and understanding of their mutational origins remains limited. Here, we systematically survey MNVs in 125,748 whole exomes and 15,708 whole genomes from the Genome Aggregation Database (gnomAD). We identify 1,792,248 MNVs across the genome with constituent variants falling within 2 bp distance of one another, including 18,756 variants with a novel combined effect on protein sequence. Finally, we estimate the relative impact of known mutational mechanisms - CpG deamination, replication error by polymerase zeta, and polymerase slippage at repeat junctions - on the generation of MNVs. Our results demonstrate the value of haplotype-aware variant annotation, and refine our understanding of genome-wide mutational mechanisms of MNVs. Multi-nucleotide variants (MNV) are genetic variants in close proximity of each other on the same haplotype whose functional impact is difficult to predict if they reside in the same codon. Here, Wang et al. use the gnomAD dataset to assemble a catalogue of MNVs and estimate their global mutation rate. [ABSTRACT FROM AUTHOR]

Published
2020
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29. The role of de novo mutations in the development of amyotrophic lateral sclerosis

Author

van Doormaal, Perry T. C., Ticozzi, Nicola, Weishaupt, Jochen H., Kenna, Kevin, Diekstra, Frank P., Verde, Federico, Andersen, Peter M., Dekker, Annelot M., Tiloca, Cinzia, Marroquin, Nicolai, Overste, Daniel J., Pensato, Viviana, Nuernberg, Peter, Pulit, Sara L., Schellevis, Raymond D., Calini, Daniela, Altmueller, Janine, Francioli, Laurent C., Muller, Bernard, Castellotti, Barbara, Motameny, Susanne, Ratti, Antonia, Wolf, Joachim, Gellera, Cinzia, Ludolph, Albert C., van den Berg, Leonard H., Kubisch, Christian, Landers, John E., Veldink, Jan H., Silani, Vincenzo, Volk, Alexander E., van Doormaal, Perry T. C., Ticozzi, Nicola, Weishaupt, Jochen H., Kenna, Kevin, Diekstra, Frank P., Verde, Federico, Andersen, Peter M., Dekker, Annelot M., Tiloca, Cinzia, Marroquin, Nicolai, Overste, Daniel J., Pensato, Viviana, Nuernberg, Peter, Pulit, Sara L., Schellevis, Raymond D., Calini, Daniela, Altmueller, Janine, Francioli, Laurent C., Muller, Bernard, Castellotti, Barbara, Motameny, Susanne, Ratti, Antonia, Wolf, Joachim, Gellera, Cinzia, Ludolph, Albert C., van den Berg, Leonard H., Kubisch, Christian, Landers, John E., Veldink, Jan H., Silani, Vincenzo, and Volk, Alexander E.

Abstract

The genetic basis combined with the sporadic occurrence of amyotrophic lateral sclerosis (ALS) suggests a role of de novo mutations in disease pathogenesis. Previous studies provided some evidence for this hypothesis; however, results were conflicting: no genes with recurrent occurring de novo mutations were identified and different pathways were postulated. In this study, we analyzed whole-exome data from 82 new patient-parents trios and combined it with the datasets of all previously published ALS trios (173 trios in total). The per patient de novo rate was not higher than expected based on the general population (P = 0.40). We showed that these mutations are not part of the previously postulated pathways, and gene-gene interaction analysis found no enrichment of interacting genes in this group (P = 0.57). Also, we were able to show that the de novo mutations in ALS patients are located in genes already prone for de novo mutations (P < 1 x 10(-15)). Although the individual effect of rare de novo mutations in specific genes could not be assessed, our results indicate that, in contrast to previous hypothesis, de novo mutations in general do not impose a major burden on ALS risk.

Published
2017
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30. Negative selection in humans and fruit flies involves synergistic epistasis

Author

Neurogenetica, Circulatory Health, CMM Groep Kaaij, Projectafdeling ALS, Brain, Regenerative Medicine and Stem Cells, ZL Neuromusculaire Ziekten Medisch, Infection & Immunity, Sohail, Mashaal, Vakhrusheva, Olga A, Sul, Jae Hoon, Pulit, Sara L, Francioli, Laurent C, van den Berg, Leonard H, Veldink, Jan H, de Bakker, Paul I W, Bazykin, Georgii A, Kondrashov, Alexey S, Sunyaev, Shamil R, Genome of the Netherlands Consortium, Neurogenetica, Circulatory Health, CMM Groep Kaaij, Projectafdeling ALS, Brain, Regenerative Medicine and Stem Cells, ZL Neuromusculaire Ziekten Medisch, Infection & Immunity, Sohail, Mashaal, Vakhrusheva, Olga A, Sul, Jae Hoon, Pulit, Sara L, Francioli, Laurent C, van den Berg, Leonard H, Veldink, Jan H, de Bakker, Paul I W, Bazykin, Georgii A, Kondrashov, Alexey S, Sunyaev, Shamil R, and Genome of the Netherlands Consortium

Published
2017

31. The role of de novo mutations in the development of amyotrophic lateral sclerosis

Author

Doormaal, Perry T.C., primary, Ticozzi, Nicola, additional, Weishaupt, Jochen H., additional, Kenna, Kevin, additional, Diekstra, Frank P., additional, Verde, Federico, additional, Andersen, Peter M., additional, Dekker, Annelot M., additional, Tiloca, Cinzia, additional, Marroquin, Nicolai, additional, Overste, Daniel J., additional, Pensato, Viviana, additional, Nürnberg, Peter, additional, Pulit, Sara L., additional, Schellevis, Raymond D., additional, Calini, Daniela, additional, Altmüller, Janine, additional, Francioli, Laurent C., additional, Muller, Bernard, additional, Castellotti, Barbara, additional, Motameny, Susanne, additional, Ratti, Antonia, additional, Wolf, Joachim, additional, Gellera, Cinzia, additional, Ludolph, Albert C., additional, den Berg, Leonard H., additional, Kubisch, Christian, additional, Landers, John E., additional, Veldink, Jan H., additional, Silani, Vincenzo, additional, and Volk, Alexander E., additional

Published
2017
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32. Characteristics of de novo structural changes in the human genome

Author

Kloosterman, Wigard P., Francioli, Laurent C., Hormozdiari, Fereydoun, Marschall, Tobias, Hehir-Kwa, Jayne Y., Abdellaoui, Abdel, Lameijer, Eric Wubbo, Moed, Matthijs H., Koval, Vyacheslav, Renkens, Ivo, Van Roosmalen, Markus J., Arp, Pascal, Karssen, Lennart C., Coe, Bradley P., Handsaker, Robert E., Suchiman, Eka D., Cuppen, Edwin, Thung, Djie Tjwan, McVey, Mitch, Wendl, Michael C., Uitterlinden, André, Van Duijn, Cornelia M., Swertz, Morris A., Wijmenga, Cisca, Van Ommen, Gert Jan B, Slagboom, P. Eline, Boomsma, Dorret I., Schönhuth, Alexander, Eichler, Evan E., De Bakker, Paul I W, Ye, Kai, Guryev, Victor, Bovenberg, Jasper A., De Craen, Anton J M, Beekman, Marian, Hofman, Albert, Willemsen, Gonneke, Wolffenbuttel, Bruce, Platteel, Mathieu, Du, Yuanping, Chen, Ruoyan, Cao, Hongzhi, Cao, Rui, Sun, Yushen, Cao, Jeremy Sujie, Van Dijk, Freerk, Neerincx, Pieter B T, Deelen, Patrick, Dijkstra, Martijn, Byelas, George, Kanterakis, Alexandros, Bot, Jan, Vermaat, Martijn, Laros, Jeroen F J, Den Dunnen, Johan T., De Knijff, Peter, Van Leeuwen, Elisa M., Amin, Najaf, Rivadeneira, Fernando, Estrada, Karol, De Ligt, Joep, Hottenga, Jouke Jan, Kattenberg, V. Mathijs, Van Enckevort, David, Mei, Hailiang, Santcroos, Mark, Van Schaik, Barbera D C, McCarroll, Steven A., Ko, Arthur, Sudmant, Peter, Nijman, Isaac J., Adult Psychiatry, Epidemiology and Data Science, ACS - Amsterdam Cardiovascular Sciences, AII - Amsterdam institute for Infection and Immunity, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ANS - Amsterdam Neuroscience, CCA -Cancer Center Amsterdam, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Internal Medicine, Epidemiology, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), and Groningen Research Institute for Asthma and COPD (GRIAC)

Subjects
Male, Netherlands Twin Register (NTR), Mutation rate, INTELLECTUAL DISABILITY, Retrotransposon, Genome of Netherlands Consortium, VARIANTS, Medical and Health Sciences, Genome, 0302 clinical medicine, INDEL Mutation, Mutation Rate, Genetics(clinical), Copy-number variation, Genetics (clinical), Genetics, 0303 health sciences, education.field_of_study, food and beverages, Genomics, Single Nucleotide, Biological Sciences, Female, Sequence Analysis, Human, Retroelements, SEQUENCING DATA, Bioinformatics, Molecular Sequence Data, Population, MUTATION-RATES, POPULATION-SCALE, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Humans, Amino Acid Sequence, Polymorphism, Indel, education, Alleles, 030304 developmental biology, COPY NUMBER VARIATION, INDIVIDUAL HUMAN, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], IDENTIFICATION, Genome, Human, Research, Human Genome, Genetic Variation, Sequence Analysis, DNA, DNA, GENE, Haplotypes, DISCOVERY, Human genome, Sequence Alignment, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 154750.pdf (Publisher’s version ) (Open Access) Small insertions and deletions (indels) and large structural variations (SVs) are major contributors to human genetic diversity and disease. However, mutation rates and characteristics of de novo indels and SVs in the general population have remained largely unexplored. We report 332 validated de novo structural changes identified in whole genomes of 250 families, including complex indels, retrotransposon insertions, and interchromosomal events. These data indicate a mutation rate of 2.94 indels (1-20 bp) and 0.16 SVs (>20 bp) per generation. De novo structural changes affect on average 4.1 kbp of genomic sequence and 29 coding bases per generation, which is 91 and 52 times more nucleotides than de novo substitutions, respectively. This contrasts with the equal genomic footprint of inherited SVs and substitutions. An excess of structural changes originated on paternal haplotypes. Additionally, we observed a nonuniform distribution of de novo SVs across offspring. These results reveal the importance of different mutational mechanisms to changes in human genome structure across generations. 01 juni 2015

Published
2015
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33. Genome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels

Author

Pulit, Sara L., Deelen, Patrick, van Enckevort, David J., Leach, Irene Mateo, Peloso, Gina M., Feitosa, Mary F., Isaacs, Aaron, van Dijk, Freerk, Hofman, Albert, Kanterakis, Alexandros, Penninx, Brenda W.J.H., Oostra, Ben A., de Geus, Eco J., Karssen, Lennart C., Willemsen, Gonneke, Postmus, Iris, Mbarek, Hamdi, Huffman, Jennifer E., Bartz, Traci M., van Leeuwen, Elisabeth M., Joshi, Peter K., Medina-Gomez, Carolina, Menelaou, Androniki, White, Charles C., Verweij, Niek, Manichaikul, Ani, Rivadeneira, Fernando, Milaneschi, Yuri, Francioli, Laurent C., Deelen, Joris, Trompet, Stella, and Franco, Oscar H.

Abstract

Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of the Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value

Published
2015
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34. A high-quality human reference panel reveals the complexity and distribution of genomic structural variants

Author

Hehir-Kwa, Jayne Y., Marschall, Tobias, Kloosterman, Wigard P., Francioli, Laurent C., Baaijens, Jasmijn A., Dijkstra, Louis J., Abdellaoui, Abdel, Koval, Vyacheslav, Thung, Djie Tjwan, Wardenaar, René, Renkens, Ivo, Coe, Bradley P., Deelen, Patrick, De Ligt, Joep, Lameijer, Eric Wubbo, Van Dijk, Freerk, Hormozdiari, Fereydoun, Uitterlinden, André G., Van Duijn, Cornelia M., Eichler, Evan E., De Bakker, Paul I.W., Swertz, Morris A., Wijmenga, Cisca, Van Ommen, Gert Jan B, Slagboom, P. Eline, Boomsma, Dorret I., Schönhuth, Alexander, Ye, Kai, Guryev, Victor, Bovenberg, Jasper A., De Craen, Anton J M, Beekman, Marian, Hofman, Albert, Willemsen, Gonneke, Wolffenbuttel, Bruce, Platteel, Mathieu, Du, Yuanping, Chen, Ruoyan, Cao, Hongzhi, Cao, Rui, Sun, Yushen, Cao, Jeremy Sujie, Neerincx, Pieter B T, Dijkstra, Martijn, Byelas, George, Kanterakis, Alexandros, Bot, Jan, Vermaat, Martijn, Laros, Jeroen F., den Dunnen, Johan T., De Knijff, Peter, Karssen, Lennart C., Van Leeuwen, Elisa M., Amin, Najaf, Rivadeneira, Fernando, Estrada, Karol, Hottenga, Jouke-Jan, Kattenberg, V. Mathijs, Van Enckevort, David, Mei, Hailiang, Santcroos, Mark, Van Schaik, Barbera D C, Handsaker, Robert E., McCarroll, Steven A., Ko, Arthur, Sudmant, Peter, Nijman, Isaac J., Hehir-Kwa, Jayne Y., Marschall, Tobias, Kloosterman, Wigard P., Francioli, Laurent C., Baaijens, Jasmijn A., Dijkstra, Louis J., Abdellaoui, Abdel, Koval, Vyacheslav, Thung, Djie Tjwan, Wardenaar, René, Renkens, Ivo, Coe, Bradley P., Deelen, Patrick, De Ligt, Joep, Lameijer, Eric Wubbo, Van Dijk, Freerk, Hormozdiari, Fereydoun, Uitterlinden, André G., Van Duijn, Cornelia M., Eichler, Evan E., De Bakker, Paul I.W., Swertz, Morris A., Wijmenga, Cisca, Van Ommen, Gert Jan B, Slagboom, P. Eline, Boomsma, Dorret I., Schönhuth, Alexander, Ye, Kai, Guryev, Victor, Bovenberg, Jasper A., De Craen, Anton J M, Beekman, Marian, Hofman, Albert, Willemsen, Gonneke, Wolffenbuttel, Bruce, Platteel, Mathieu, Du, Yuanping, Chen, Ruoyan, Cao, Hongzhi, Cao, Rui, Sun, Yushen, Cao, Jeremy Sujie, Neerincx, Pieter B T, Dijkstra, Martijn, Byelas, George, Kanterakis, Alexandros, Bot, Jan, Vermaat, Martijn, Laros, Jeroen F., den Dunnen, Johan T., De Knijff, Peter, Karssen, Lennart C., Van Leeuwen, Elisa M., Amin, Najaf, Rivadeneira, Fernando, Estrada, Karol, Hottenga, Jouke-Jan, Kattenberg, V. Mathijs, Van Enckevort, David, Mei, Hailiang, Santcroos, Mark, Van Schaik, Barbera D C, Handsaker, Robert E., McCarroll, Steven A., Ko, Arthur, Sudmant, Peter, and Nijman, Isaac J.

Published
2016

35. A framework for the detection of de novo mutations in family-based sequencing data

Author

Francioli, Laurent C., Cretu-Stancu, Mircea, Garimella, Kiran V., Fromer, Menachem, Kloosterman, Wigard P., Samocha, Kaitlin E., Neale, Benjamin M., Daly, Mark J., Banks, Eric, DePristo, Mark A., de Bakker, Paul IW, Francioli, Laurent C., Cretu-Stancu, Mircea, Garimella, Kiran V., Fromer, Menachem, Kloosterman, Wigard P., Samocha, Kaitlin E., Neale, Benjamin M., Daly, Mark J., Banks, Eric, DePristo, Mark A., and de Bakker, Paul IW

Published
2016

36. A high-quality human reference panel reveals the complexity and distribution of genomic structural variants

Author

Genetica, CMM Groep Kloosterman, Child Health, Cancer, CMM Groep Kaaij, CMM Groep Cuppen, CMM Groep De Ridder, Epi Methoden Team 2, Infection & Immunity, Circulatory Health, Hubrecht Institute with UMC, Genetica Medische Informatica, Genetica Sectie Genoomdiagnostiek, Hehir-Kwa, Jayne Y., Marschall, Tobias, Kloosterman, Wigard P., Francioli, Laurent C., Baaijens, Jasmijn A., Dijkstra, Louis J., Abdellaoui, Abdel, Koval, Vyacheslav, Thung, Djie Tjwan, Wardenaar, René, Renkens, Ivo, Coe, Bradley P., Deelen, Patrick, De Ligt, Joep, Lameijer, Eric Wubbo, Van Dijk, Freerk, Hormozdiari, Fereydoun, Uitterlinden, André G., Van Duijn, Cornelia M., Eichler, Evan E., De Bakker, Paul I.W., Swertz, Morris A., Wijmenga, Cisca, Van Ommen, Gert Jan B, Slagboom, P. Eline, Boomsma, Dorret I., Schönhuth, Alexander, Ye, Kai, Guryev, Victor, Bovenberg, Jasper A., De Craen, Anton J M, Beekman, Marian, Hofman, Albert, Willemsen, Gonneke, Wolffenbuttel, Bruce, Platteel, Mathieu, Du, Yuanping, Chen, Ruoyan, Cao, Hongzhi, Cao, Rui, Sun, Yushen, Cao, Jeremy Sujie, Neerincx, Pieter B T, Dijkstra, Martijn, Byelas, George, Kanterakis, Alexandros, Bot, Jan, Vermaat, Martijn, Laros, Jeroen F., den Dunnen, Johan T., De Knijff, Peter, Karssen, Lennart C., Van Leeuwen, Elisa M., Amin, Najaf, Rivadeneira, Fernando, Estrada, Karol, Hottenga, Jouke-Jan, Kattenberg, V. Mathijs, Van Enckevort, David, Mei, Hailiang, Santcroos, Mark, Van Schaik, Barbera D C, Handsaker, Robert E., McCarroll, Steven A., Ko, Arthur, Sudmant, Peter, Nijman, Isaac J., Genetica, CMM Groep Kloosterman, Child Health, Cancer, CMM Groep Kaaij, CMM Groep Cuppen, CMM Groep De Ridder, Epi Methoden Team 2, Infection & Immunity, Circulatory Health, Hubrecht Institute with UMC, Genetica Medische Informatica, Genetica Sectie Genoomdiagnostiek, Hehir-Kwa, Jayne Y., Marschall, Tobias, Kloosterman, Wigard P., Francioli, Laurent C., Baaijens, Jasmijn A., Dijkstra, Louis J., Abdellaoui, Abdel, Koval, Vyacheslav, Thung, Djie Tjwan, Wardenaar, René, Renkens, Ivo, Coe, Bradley P., Deelen, Patrick, De Ligt, Joep, Lameijer, Eric Wubbo, Van Dijk, Freerk, Hormozdiari, Fereydoun, Uitterlinden, André G., Van Duijn, Cornelia M., Eichler, Evan E., De Bakker, Paul I.W., Swertz, Morris A., Wijmenga, Cisca, Van Ommen, Gert Jan B, Slagboom, P. Eline, Boomsma, Dorret I., Schönhuth, Alexander, Ye, Kai, Guryev, Victor, Bovenberg, Jasper A., De Craen, Anton J M, Beekman, Marian, Hofman, Albert, Willemsen, Gonneke, Wolffenbuttel, Bruce, Platteel, Mathieu, Du, Yuanping, Chen, Ruoyan, Cao, Hongzhi, Cao, Rui, Sun, Yushen, Cao, Jeremy Sujie, Neerincx, Pieter B T, Dijkstra, Martijn, Byelas, George, Kanterakis, Alexandros, Bot, Jan, Vermaat, Martijn, Laros, Jeroen F., den Dunnen, Johan T., De Knijff, Peter, Karssen, Lennart C., Van Leeuwen, Elisa M., Amin, Najaf, Rivadeneira, Fernando, Estrada, Karol, Hottenga, Jouke-Jan, Kattenberg, V. Mathijs, Van Enckevort, David, Mei, Hailiang, Santcroos, Mark, Van Schaik, Barbera D C, Handsaker, Robert E., McCarroll, Steven A., Ko, Arthur, Sudmant, Peter, and Nijman, Isaac J.

Published
2016

37. Transmission of human mtDNA heteroplasmy in the genome of the Netherlands families: Support for a variable-size bottleneck

Author

Epidemiology & Health Economics, CMM Groep Kaaij, Brain, Infection & Immunity, Circulatory Health, JC onderzoeksprogramma Methodologie, CMM Groep Cuppen, Cancer, CMM Groep Kloosterman, Child Health, Genetica Medische Informatica, Genetica Sectie Genoomdiagnostiek, Li, Mingkun, Rothwell, Rebecca, Vermaat, Martijn, Wachsmuth, Manja, Schröder, Roland, Laros, Jeroen F J, Van Oven, Mannis, De Bakker, Paul I W, Bovenberg, Jasper A., Van Duijn, Cornelia M., Van Ommen, Gert Jan B, Slagboom, P. Eline, Swertz, Morris A., Wijmenga, Cisca, Kayser, Manfred, Boomsma, Dorret I., Zöllner, Sebastian, De Knijff, Peter, Stoneking, Mark, De Craen, Anton J M, Beekman, Marian, Hofman, Albert, Willemsen, Gonneke, Wolffenbuttel, Bruce, Platteel, Mathieu, Du, Yuanping, Chen, Ruoyan, Cao, Hongzhi, Cao, Rui, Sun, Yushen, Cao, Jeremy Sujie, Van Dijk, Freerk, Neerincx, Pieter B T, Deelen, Patrick, Dijkstra, Martijn, Byelas, George, Kanterakis, Alexandros, Bot, Jan, Ye, Kai, Lameijer, Eric Wubbo, Den Dunnen, Johan T., Karssen, Lennart C., Van Leeuwen, Elisa M., Amin, Najaf, Koval, Vyacheslav, Rivadeneira, Fernando, Estrada, Karol, Hehir-Kwa, Jayne Y., De Ligt, Joep, Abdellaoui, Abdel, Hottenga, Jouke Jan, Kattenberg, V. Mathijs, Van Enckevort, David, Mei, Hailiang, Santcroos, Mark, Van Schaik, Barbera D C, Handsaker, Robert E., McCarroll, Steven A., Eichler, Evan E., Ko, Arthur, Sudmant, Peter, Francioli, Laurent C., Kloosterman, Wigard P., Nijman, Isaac J., Guryev, Victor, Epidemiology & Health Economics, CMM Groep Kaaij, Brain, Infection & Immunity, Circulatory Health, JC onderzoeksprogramma Methodologie, CMM Groep Cuppen, Cancer, CMM Groep Kloosterman, Child Health, Genetica Medische Informatica, Genetica Sectie Genoomdiagnostiek, Li, Mingkun, Rothwell, Rebecca, Vermaat, Martijn, Wachsmuth, Manja, Schröder, Roland, Laros, Jeroen F J, Van Oven, Mannis, De Bakker, Paul I W, Bovenberg, Jasper A., Van Duijn, Cornelia M., Van Ommen, Gert Jan B, Slagboom, P. Eline, Swertz, Morris A., Wijmenga, Cisca, Kayser, Manfred, Boomsma, Dorret I., Zöllner, Sebastian, De Knijff, Peter, Stoneking, Mark, De Craen, Anton J M, Beekman, Marian, Hofman, Albert, Willemsen, Gonneke, Wolffenbuttel, Bruce, Platteel, Mathieu, Du, Yuanping, Chen, Ruoyan, Cao, Hongzhi, Cao, Rui, Sun, Yushen, Cao, Jeremy Sujie, Van Dijk, Freerk, Neerincx, Pieter B T, Deelen, Patrick, Dijkstra, Martijn, Byelas, George, Kanterakis, Alexandros, Bot, Jan, Ye, Kai, Lameijer, Eric Wubbo, Den Dunnen, Johan T., Karssen, Lennart C., Van Leeuwen, Elisa M., Amin, Najaf, Koval, Vyacheslav, Rivadeneira, Fernando, Estrada, Karol, Hehir-Kwa, Jayne Y., De Ligt, Joep, Abdellaoui, Abdel, Hottenga, Jouke Jan, Kattenberg, V. Mathijs, Van Enckevort, David, Mei, Hailiang, Santcroos, Mark, Van Schaik, Barbera D C, Handsaker, Robert E., McCarroll, Steven A., Eichler, Evan E., Ko, Arthur, Sudmant, Peter, Francioli, Laurent C., Kloosterman, Wigard P., Nijman, Isaac J., and Guryev, Victor

Published
2016

38. A framework for the detection of de novo mutations in family-based sequencing data

Author

CMM Groep Kaaij, UMC Utrecht, Circulatory Health, CMM Groep Kloosterman, Child Health, Cancer, Brain, Infection & Immunity, Francioli, Laurent C., Cretu-Stancu, Mircea, Garimella, Kiran V., Fromer, Menachem, Kloosterman, Wigard P., Samocha, Kaitlin E., Neale, Benjamin M., Daly, Mark J., Banks, Eric, DePristo, Mark A., de Bakker, Paul IW, CMM Groep Kaaij, UMC Utrecht, Circulatory Health, CMM Groep Kloosterman, Child Health, Cancer, Brain, Infection & Immunity, Francioli, Laurent C., Cretu-Stancu, Mircea, Garimella, Kiran V., Fromer, Menachem, Kloosterman, Wigard P., Samocha, Kaitlin E., Neale, Benjamin M., Daly, Mark J., Banks, Eric, DePristo, Mark A., and de Bakker, Paul IW

Published
2016

39. Genome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels

Author

Van Leeuwen, Elisabeth M., Karssen, Lennart C., Deelen, Joris, Isaacs, Aaron, Medina-Gomez, Carolina, Mbarek, Hamdi, Kanterakis, Alexandros, Trompet, Stella, Postmus, Iris, Verweij, Niek, Van Enckevort, David J., Huffman, Jennifer E., White, Charles C., Feitosa, Mary F., Bartz, Traci M., Manichaikul, Ani, Joshi, Peter K., Peloso, Gina M., Deelen, Patrick, Van Dijk, Freerk, Willemsen, Gonneke, De Geus, Eco J., Milaneschi, Yuri, Penninx, Brenda W J H, Francioli, Laurent C., Menelaou, Androniki, Pulit, Sara L., Rivadeneira, Fernando, Hofman, Albert, Oostra, Ben A., Franco, Oscar H., Leach, Irene Mateo, Beekman, Marian, De Craen, Anton J M, Uh, Hae Won, Trochet, Holly, Hocking, Lynne J., Porteous, David J., Sattar, Naveed, Packard, Chris J., Buckley, Brendan M., Brody, Jennifer A., Bis, Joshua C., Rotter, Jerome I., Mychaleckyj, Josyf C., Campbell, Harry, Duan, Qing, Lange, Leslie A., Wilson, James F., Hayward, Caroline, Polasek, Ozren, Vitart, Veronique, Rudan, Igor, Wright, Alan F., Rich, Stephen S., Psaty, Bruce M., Borecki, Ingrid B., Kearney, Patricia M., Stott, David J., Cupples, L. Adrienne, Jukema, J. Wouter, Van Der Harst, Pim, Sijbrands, Eric J., Hottenga, Jouke Jan, Uitterlinden, Andre G., Swertz, Morris A., Van Ommen, Gert Jan B, De Bakker, Paul I W, Eline Slagboom, P., Boomsma, Dorret I., Wijmenga, Cisca, Van Duijn, Cornelia M., Neerincx, Pieter B T, Elbers, Clara C., Palamara, Pier Francesco, Peer, Itsik, Abdellaoui, Abdel, Kloosterman, Wigard P., Van Oven, Mannis, Vermaat, Martijn, Li, Mingkun, Laros, Jeroen F J, Stoneking, Mark, De Knijff, Peter, Kayser, Manfred, Veldink, Jan H., Van Den Berg, Leonard H., Byelas, Heorhiy, Den Dunnen, Johan T., Dijkstra, Martijn, Amin, Najaf, Van Der Velde, K. Joeri, Van Setten, Jessica, Kattenberg, Mathijs, Van Schaik, Barbera D C, Bot, Jan, Nijman, Isaäc J., Mei, Hailiang, Koval, Vyacheslav, Ye, Kai, Lameijer, Eric Wubbo, Moed, Matthijs H., Hehir-Kwa, Jayne Y., Handsaker, Robert E., Sunyaev, Shamil R., Sohail, Mashaal, Hormozdiari, Fereydoun, Marschall, Tobias, Schönhuth, Alexander, Guryev, Victor, Suchiman, H. Eka D, Wolffenbuttel, Bruce H., Platteel, Mathieu, Pitts, Steven J., Potluri, Shobha, Cox, David R., Li, Qibin, Li, Yingrui, Du, Yuanping, Chen, Ruoyan, Cao, Hongzhi, Li, Ning, Cao, Sujie, Wang, Jun, Bovenberg, Jasper A., Van Leeuwen, Elisabeth M., Karssen, Lennart C., Deelen, Joris, Isaacs, Aaron, Medina-Gomez, Carolina, Mbarek, Hamdi, Kanterakis, Alexandros, Trompet, Stella, Postmus, Iris, Verweij, Niek, Van Enckevort, David J., Huffman, Jennifer E., White, Charles C., Feitosa, Mary F., Bartz, Traci M., Manichaikul, Ani, Joshi, Peter K., Peloso, Gina M., Deelen, Patrick, Van Dijk, Freerk, Willemsen, Gonneke, De Geus, Eco J., Milaneschi, Yuri, Penninx, Brenda W J H, Francioli, Laurent C., Menelaou, Androniki, Pulit, Sara L., Rivadeneira, Fernando, Hofman, Albert, Oostra, Ben A., Franco, Oscar H., Leach, Irene Mateo, Beekman, Marian, De Craen, Anton J M, Uh, Hae Won, Trochet, Holly, Hocking, Lynne J., Porteous, David J., Sattar, Naveed, Packard, Chris J., Buckley, Brendan M., Brody, Jennifer A., Bis, Joshua C., Rotter, Jerome I., Mychaleckyj, Josyf C., Campbell, Harry, Duan, Qing, Lange, Leslie A., Wilson, James F., Hayward, Caroline, Polasek, Ozren, Vitart, Veronique, Rudan, Igor, Wright, Alan F., Rich, Stephen S., Psaty, Bruce M., Borecki, Ingrid B., Kearney, Patricia M., Stott, David J., Cupples, L. Adrienne, Jukema, J. Wouter, Van Der Harst, Pim, Sijbrands, Eric J., Hottenga, Jouke Jan, Uitterlinden, Andre G., Swertz, Morris A., Van Ommen, Gert Jan B, De Bakker, Paul I W, Eline Slagboom, P., Boomsma, Dorret I., Wijmenga, Cisca, Van Duijn, Cornelia M., Neerincx, Pieter B T, Elbers, Clara C., Palamara, Pier Francesco, Peer, Itsik, Abdellaoui, Abdel, Kloosterman, Wigard P., Van Oven, Mannis, Vermaat, Martijn, Li, Mingkun, Laros, Jeroen F J, Stoneking, Mark, De Knijff, Peter, Kayser, Manfred, Veldink, Jan H., Van Den Berg, Leonard H., Byelas, Heorhiy, Den Dunnen, Johan T., Dijkstra, Martijn, Amin, Najaf, Van Der Velde, K. Joeri, Van Setten, Jessica, Kattenberg, Mathijs, Van Schaik, Barbera D C, Bot, Jan, Nijman, Isaäc J., Mei, Hailiang, Koval, Vyacheslav, Ye, Kai, Lameijer, Eric Wubbo, Moed, Matthijs H., Hehir-Kwa, Jayne Y., Handsaker, Robert E., Sunyaev, Shamil R., Sohail, Mashaal, Hormozdiari, Fereydoun, Marschall, Tobias, Schönhuth, Alexander, Guryev, Victor, Suchiman, H. Eka D, Wolffenbuttel, Bruce H., Platteel, Mathieu, Pitts, Steven J., Potluri, Shobha, Cox, David R., Li, Qibin, Li, Yingrui, Du, Yuanping, Chen, Ruoyan, Cao, Hongzhi, Li, Ning, Cao, Sujie, Wang, Jun, and Bovenberg, Jasper A.

Abstract

Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (∼35,000 samples) with the population-specific reference panel created by the Genome of the Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value -4), including a rare missense variant in ABCA6 (rs77542162, p.Cys1359Arg, frequency 0.034), which is predicted to be deleterious. The frequency of this ABCA6 variant is 3.65-fold increased in the Dutch and its effect (βLDL-C =0.135, βTC =0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.

Published
2015

40. Genome-wide patterns and properties of de novo mutations in humans

Author

Francioli, Laurent C., Polak, Paz P., Koren, Amnon, Menelaou, A., Chun, Sung, Renkens, I.J., Van Duijn, Cornelia M., Swertz, Morris, Wijmenga, Cisca, Van Ommen, Gertjan, Slagboom, P. Eline, Boomsma, Dorret I., Ye, Kai, Guryev, Victor, Arndt, Peter F., Kloosterman, Wigard P., De Bakker, Paul I W, Sunyaev, Shamil R., Francioli, Laurent C., Polak, Paz P., Koren, Amnon, Menelaou, A., Chun, Sung, Renkens, I.J., Van Duijn, Cornelia M., Swertz, Morris, Wijmenga, Cisca, Van Ommen, Gertjan, Slagboom, P. Eline, Boomsma, Dorret I., Ye, Kai, Guryev, Victor, Arndt, Peter F., Kloosterman, Wigard P., De Bakker, Paul I W, and Sunyaev, Shamil R.

Published
2015

41. Leveraging Distant Relatedness to Quantify Human Mutation and Gene-Conversion Rates

Author

CMM Groep Kaaij, JC onderzoeksprogramma Methodologie, Cancer, Palamara, Pier Francesco, Francioli, Laurent C, Wilton, Peter R, Genovese, Giulio, Gusev, Alexander, Finucane, Hilary K, Sankararaman, Sriram, Sunyaev, Shamil R, de Bakker, Paul I W, Wakeley, John, Pe'er, Itsik, Price, Alkes L, Genome of the Netherlands Consortium, CMM Groep Kaaij, JC onderzoeksprogramma Methodologie, Cancer, Palamara, Pier Francesco, Francioli, Laurent C, Wilton, Peter R, Genovese, Giulio, Gusev, Alexander, Finucane, Hilary K, Sankararaman, Sriram, Sunyaev, Shamil R, de Bakker, Paul I W, Wakeley, John, Pe'er, Itsik, Price, Alkes L, and Genome of the Netherlands Consortium

Published
2015

42. Genome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels

Author

CMM Groep Kaaij, CMM Groep Kloosterman, Child Health, Cancer, ZL Neuromusculaire Ziekten Medisch, Experimentele Afd. Cardiologie 1, CMM Groep Cuppen, JC onderzoeksprogramma Methodologie, Van Leeuwen, Elisabeth M., Karssen, Lennart C., Deelen, Joris, Isaacs, Aaron, Medina-Gomez, Carolina, Mbarek, Hamdi, Kanterakis, Alexandros, Trompet, Stella, Postmus, Iris, Verweij, Niek, Van Enckevort, David J., Huffman, Jennifer E., White, Charles C., Feitosa, Mary F., Bartz, Traci M., Manichaikul, Ani, Joshi, Peter K., Peloso, Gina M., Deelen, Patrick, Van Dijk, Freerk, Willemsen, Gonneke, De Geus, Eco J., Milaneschi, Yuri, Penninx, Brenda W J H, Francioli, Laurent C., Menelaou, Androniki, Pulit, Sara L., Rivadeneira, Fernando, Hofman, Albert, Oostra, Ben A., Franco, Oscar H., Leach, Irene Mateo, Beekman, Marian, De Craen, Anton J M, Uh, Hae Won, Trochet, Holly, Hocking, Lynne J., Porteous, David J., Sattar, Naveed, Packard, Chris J., Buckley, Brendan M., Brody, Jennifer A., Bis, Joshua C., Rotter, Jerome I., Mychaleckyj, Josyf C., Campbell, Harry, Duan, Qing, Lange, Leslie A., Wilson, James F., Hayward, Caroline, Polasek, Ozren, Vitart, Veronique, Rudan, Igor, Wright, Alan F., Rich, Stephen S., Psaty, Bruce M., Borecki, Ingrid B., Kearney, Patricia M., Stott, David J., Cupples, L. Adrienne, Jukema, J. Wouter, Van Der Harst, Pim, Sijbrands, Eric J., Hottenga, Jouke Jan, Uitterlinden, Andre G., Swertz, Morris A., Van Ommen, Gert Jan B, De Bakker, Paul I W, Eline Slagboom, P., Boomsma, Dorret I., Wijmenga, Cisca, Van Duijn, Cornelia M., Neerincx, Pieter B T, Elbers, Clara C., Palamara, Pier Francesco, Peer, Itsik, Abdellaoui, Abdel, Kloosterman, Wigard P., Van Oven, Mannis, Vermaat, Martijn, Li, Mingkun, Laros, Jeroen F J, Stoneking, Mark, De Knijff, Peter, Kayser, Manfred, Veldink, Jan H., Van Den Berg, Leonard H., Byelas, Heorhiy, Den Dunnen, Johan T., Dijkstra, Martijn, Amin, Najaf, Van Der Velde, K. Joeri, Van Setten, Jessica, Kattenberg, Mathijs, Van Schaik, Barbera D C, Bot, Jan, Nijman, Isaäc J., Mei, Hailiang, Koval, Vyacheslav, Ye, Kai, Lameijer, Eric Wubbo, Moed, Matthijs H., Hehir-Kwa, Jayne Y., Handsaker, Robert E., Sunyaev, Shamil R., Sohail, Mashaal, Hormozdiari, Fereydoun, Marschall, Tobias, Schönhuth, Alexander, Guryev, Victor, Suchiman, H. Eka D, Wolffenbuttel, Bruce H., Platteel, Mathieu, Pitts, Steven J., Potluri, Shobha, Cox, David R., Li, Qibin, Li, Yingrui, Du, Yuanping, Chen, Ruoyan, Cao, Hongzhi, Li, Ning, Cao, Sujie, Wang, Jun, Bovenberg, Jasper A., de Bakker, Paul I W, CMM Groep Kaaij, CMM Groep Kloosterman, Child Health, Cancer, ZL Neuromusculaire Ziekten Medisch, Experimentele Afd. Cardiologie 1, CMM Groep Cuppen, JC onderzoeksprogramma Methodologie, Van Leeuwen, Elisabeth M., Karssen, Lennart C., Deelen, Joris, Isaacs, Aaron, Medina-Gomez, Carolina, Mbarek, Hamdi, Kanterakis, Alexandros, Trompet, Stella, Postmus, Iris, Verweij, Niek, Van Enckevort, David J., Huffman, Jennifer E., White, Charles C., Feitosa, Mary F., Bartz, Traci M., Manichaikul, Ani, Joshi, Peter K., Peloso, Gina M., Deelen, Patrick, Van Dijk, Freerk, Willemsen, Gonneke, De Geus, Eco J., Milaneschi, Yuri, Penninx, Brenda W J H, Francioli, Laurent C., Menelaou, Androniki, Pulit, Sara L., Rivadeneira, Fernando, Hofman, Albert, Oostra, Ben A., Franco, Oscar H., Leach, Irene Mateo, Beekman, Marian, De Craen, Anton J M, Uh, Hae Won, Trochet, Holly, Hocking, Lynne J., Porteous, David J., Sattar, Naveed, Packard, Chris J., Buckley, Brendan M., Brody, Jennifer A., Bis, Joshua C., Rotter, Jerome I., Mychaleckyj, Josyf C., Campbell, Harry, Duan, Qing, Lange, Leslie A., Wilson, James F., Hayward, Caroline, Polasek, Ozren, Vitart, Veronique, Rudan, Igor, Wright, Alan F., Rich, Stephen S., Psaty, Bruce M., Borecki, Ingrid B., Kearney, Patricia M., Stott, David J., Cupples, L. Adrienne, Jukema, J. Wouter, Van Der Harst, Pim, Sijbrands, Eric J., Hottenga, Jouke Jan, Uitterlinden, Andre G., Swertz, Morris A., Van Ommen, Gert Jan B, De Bakker, Paul I W, Eline Slagboom, P., Boomsma, Dorret I., Wijmenga, Cisca, Van Duijn, Cornelia M., Neerincx, Pieter B T, Elbers, Clara C., Palamara, Pier Francesco, Peer, Itsik, Abdellaoui, Abdel, Kloosterman, Wigard P., Van Oven, Mannis, Vermaat, Martijn, Li, Mingkun, Laros, Jeroen F J, Stoneking, Mark, De Knijff, Peter, Kayser, Manfred, Veldink, Jan H., Van Den Berg, Leonard H., Byelas, Heorhiy, Den Dunnen, Johan T., Dijkstra, Martijn, Amin, Najaf, Van Der Velde, K. Joeri, Van Setten, Jessica, Kattenberg, Mathijs, Van Schaik, Barbera D C, Bot, Jan, Nijman, Isaäc J., Mei, Hailiang, Koval, Vyacheslav, Ye, Kai, Lameijer, Eric Wubbo, Moed, Matthijs H., Hehir-Kwa, Jayne Y., Handsaker, Robert E., Sunyaev, Shamil R., Sohail, Mashaal, Hormozdiari, Fereydoun, Marschall, Tobias, Schönhuth, Alexander, Guryev, Victor, Suchiman, H. Eka D, Wolffenbuttel, Bruce H., Platteel, Mathieu, Pitts, Steven J., Potluri, Shobha, Cox, David R., Li, Qibin, Li, Yingrui, Du, Yuanping, Chen, Ruoyan, Cao, Hongzhi, Li, Ning, Cao, Sujie, Wang, Jun, Bovenberg, Jasper A., and de Bakker, Paul I W

Published
2015

43. Genome-wide patterns and properties of de novo mutations in humans

Author

CMM Groep Kaaij, Genetica, CMM Groep Kloosterman, Child Health, Cancer, Brain, Infection & Immunity, JC onderzoeksprogramma Methodologie, Circulatory Health, Francioli, Laurent C., Polak, Paz P., Koren, Amnon, Menelaou, A., Chun, Sung, Renkens, I.J., Van Duijn, Cornelia M., Swertz, Morris, Wijmenga, Cisca, Van Ommen, Gertjan, Slagboom, P. Eline, Boomsma, Dorret I., Ye, Kai, Guryev, Victor, Arndt, Peter F., Kloosterman, Wigard P., De Bakker, Paul I W, Sunyaev, Shamil R., CMM Groep Kaaij, Genetica, CMM Groep Kloosterman, Child Health, Cancer, Brain, Infection & Immunity, JC onderzoeksprogramma Methodologie, Circulatory Health, Francioli, Laurent C., Polak, Paz P., Koren, Amnon, Menelaou, A., Chun, Sung, Renkens, I.J., Van Duijn, Cornelia M., Swertz, Morris, Wijmenga, Cisca, Van Ommen, Gertjan, Slagboom, P. Eline, Boomsma, Dorret I., Ye, Kai, Guryev, Victor, Arndt, Peter F., Kloosterman, Wigard P., De Bakker, Paul I W, and Sunyaev, Shamil R.

Published
2015

44. Characteristics of de novo structural changes in the human genome

Author

CMM Groep Kloosterman, Child Health, Cancer, Genetica, CMM Sectie Genomics and Bioinformatics, Hubrecht Institute with UMC, JC onderzoeksprogramma Methodologie, Epi Methoden Team 1, Kloosterman, Wigard P., Francioli, Laurent C., Hormozdiari, Fereydoun, Marschall, Tobias, Hehir-Kwa, Jayne Y., Abdellaoui, Abdel, Lameijer, Eric Wubbo, Moed, Matthijs H., Koval, Vyacheslav, Renkens, Ivo, Van Roosmalen, Markus J., Arp, Pascal, Karssen, Lennart C., Coe, Bradley P., Handsaker, Robert E., Suchiman, Eka D., Cuppen, Edwin, Thung, Djie Tjwan, McVey, Mitch, Wendl, Michael C., Uitterlinden, André, Van Duijn, Cornelia M., Swertz, Morris A., Wijmenga, Cisca, Van Ommen, Gert Jan B, Slagboom, P. Eline, Boomsma, Dorret I., Schönhuth, Alexander, Eichler, Evan E., De Bakker, Paul I W, Ye, Kai, Guryev, Victor, Bovenberg, Jasper A., De Craen, Anton J M, Beekman, Marian, Hofman, Albert, Willemsen, Gonneke, Wolffenbuttel, Bruce, Platteel, Mathieu, Du, Yuanping, Chen, Ruoyan, Cao, Hongzhi, Cao, Rui, Sun, Yushen, Cao, Jeremy Sujie, Van Dijk, Freerk, Neerincx, Pieter B T, Deelen, Patrick, Dijkstra, Martijn, Byelas, George, Kanterakis, Alexandros, Bot, Jan, Vermaat, Martijn, Laros, Jeroen F J, Den Dunnen, Johan T., De Knijff, Peter, Van Leeuwen, Elisa M., Amin, Najaf, Rivadeneira, Fernando, Estrada, Karol, De Ligt, Joep, Hottenga, Jouke Jan, Kattenberg, V. Mathijs, Van Enckevort, David, Mei, Hailiang, Santcroos, Mark, Van Schaik, Barbera D C, McCarroll, Steven A., Ko, Arthur, Sudmant, Peter, Nijman, Isaac J., CMM Groep Kloosterman, Child Health, Cancer, Genetica, CMM Sectie Genomics and Bioinformatics, Hubrecht Institute with UMC, JC onderzoeksprogramma Methodologie, Epi Methoden Team 1, Kloosterman, Wigard P., Francioli, Laurent C., Hormozdiari, Fereydoun, Marschall, Tobias, Hehir-Kwa, Jayne Y., Abdellaoui, Abdel, Lameijer, Eric Wubbo, Moed, Matthijs H., Koval, Vyacheslav, Renkens, Ivo, Van Roosmalen, Markus J., Arp, Pascal, Karssen, Lennart C., Coe, Bradley P., Handsaker, Robert E., Suchiman, Eka D., Cuppen, Edwin, Thung, Djie Tjwan, McVey, Mitch, Wendl, Michael C., Uitterlinden, André, Van Duijn, Cornelia M., Swertz, Morris A., Wijmenga, Cisca, Van Ommen, Gert Jan B, Slagboom, P. Eline, Boomsma, Dorret I., Schönhuth, Alexander, Eichler, Evan E., De Bakker, Paul I W, Ye, Kai, Guryev, Victor, Bovenberg, Jasper A., De Craen, Anton J M, Beekman, Marian, Hofman, Albert, Willemsen, Gonneke, Wolffenbuttel, Bruce, Platteel, Mathieu, Du, Yuanping, Chen, Ruoyan, Cao, Hongzhi, Cao, Rui, Sun, Yushen, Cao, Jeremy Sujie, Van Dijk, Freerk, Neerincx, Pieter B T, Deelen, Patrick, Dijkstra, Martijn, Byelas, George, Kanterakis, Alexandros, Bot, Jan, Vermaat, Martijn, Laros, Jeroen F J, Den Dunnen, Johan T., De Knijff, Peter, Van Leeuwen, Elisa M., Amin, Najaf, Rivadeneira, Fernando, Estrada, Karol, De Ligt, Joep, Hottenga, Jouke Jan, Kattenberg, V. Mathijs, Van Enckevort, David, Mei, Hailiang, Santcroos, Mark, Van Schaik, Barbera D C, McCarroll, Steven A., Ko, Arthur, Sudmant, Peter, and Nijman, Isaac J.

Published
2015

45. The Genome of the Netherlands:design, and project goals

Author

Boomsma, Dorret I., Wijmenga, Cisca, Slagboom, Eline P., Swertz, Morris A., Karssen, Lennart C., Abdellaoui, Abdel, Ye, Kai, Guryev, Victor, Vermaat, Martijn, van Dijk, Freerk, Francioli, Laurent C., Hottenga, Jouke Jan, Laros, Jeroen F. J., Li, Qibin, Li, Yingrui, Cao, Hongzhi, Chen, Ruoyan, Du, Yuanping, Li, Ning, Cao, Sujie, van Setten, Jessica, Menelaou, Androniki, Pulit, Sara L., Hehir-Kwa, Jayne Y., Beekman, Marian, Elbers, Clara C., Byelas, Heorhiy, de Craen, Anton J. M., Deelen, Patrick, Dijkstra, Martijn, den Dunnen, Johan T., de Knijff, Peter, Houwing-Duistermaat, Jeanine, Koval, Vyacheslav, Estrada, Karol, Hofman, Albert, Kanterakis, Alexandros, van Enckevort, David, Mai, Hailiang, Kattenberg, Mathijs, van Leeuwen, Elisabeth M., Neerincx, Pieter B. T., Oostra, Ben, Rivadeneira, Fernanodo, Suchiman, Eka H. D., Uitterlinden, Andre G., Willemsen, Gonneke, Wolffenbuttel, Bruce H., Wang, Jun, de Bakker, Paul I. W., van Ommen, Gert-Jan, van Duijn, Cornelia M., Boomsma, Dorret I., Wijmenga, Cisca, Slagboom, Eline P., Swertz, Morris A., Karssen, Lennart C., Abdellaoui, Abdel, Ye, Kai, Guryev, Victor, Vermaat, Martijn, van Dijk, Freerk, Francioli, Laurent C., Hottenga, Jouke Jan, Laros, Jeroen F. J., Li, Qibin, Li, Yingrui, Cao, Hongzhi, Chen, Ruoyan, Du, Yuanping, Li, Ning, Cao, Sujie, van Setten, Jessica, Menelaou, Androniki, Pulit, Sara L., Hehir-Kwa, Jayne Y., Beekman, Marian, Elbers, Clara C., Byelas, Heorhiy, de Craen, Anton J. M., Deelen, Patrick, Dijkstra, Martijn, den Dunnen, Johan T., de Knijff, Peter, Houwing-Duistermaat, Jeanine, Koval, Vyacheslav, Estrada, Karol, Hofman, Albert, Kanterakis, Alexandros, van Enckevort, David, Mai, Hailiang, Kattenberg, Mathijs, van Leeuwen, Elisabeth M., Neerincx, Pieter B. T., Oostra, Ben, Rivadeneira, Fernanodo, Suchiman, Eka H. D., Uitterlinden, Andre G., Willemsen, Gonneke, Wolffenbuttel, Bruce H., Wang, Jun, de Bakker, Paul I. W., van Ommen, Gert-Jan, and van Duijn, Cornelia M.

Published
2014

46. Whole-genome sequence variation, population structure and demographic history of the Dutch population

Author

Francioli, Laurent C., Menelaou, Andronild, Pulit, Sara L., Van Dijk, Freerk, Palamara, Pier Francesco, Elbers, Clara C., Neerincx, Pieter B. T., Ye, Kai, Guryev, Victor, Kloosterman, Wigard P., Deelen, Patrick, Abdellaoui, Abdel, Van Leeuwen, Elisabeth M., Van Oven, Mannis, Vermaat, Martijn, Li, Mingkun, Laros, Jeroen F. J., Karssen, Lennart C., Kanterakis, Alexandros, Amin, Najaf, Hottenga, Jouke Jan, Lameijer, Eric-Wubbo, Kattenberg, Mathijs, Dijkstra, Martijn, Byelas, Heorhiy, Van Settenl, Jessica, Van Schaik, Barbera D. C., Bot, Jan, Nijman, Isaac J., Renkens, Ivo, Marscha, Tobias, Schonhuth, Alexander, Hehir-Kwa, Jayne Y., Handsaker, Robert E., Polak, Paz, Sohail, Mashaal, Vuzman, Dana, Hormozdiari, Fereydoun, Van Enckevort, David, Mei, Hailiang, Koval, Vyacheslav, Moed, Ma-Tthijs H., Van der Velde, K. Joeri, Rivadeneira, Fernando, Estrada, Karol, Medina-Gomez, Carolina, Isaacs, Aaron, McCarroll, Steven A., Beekrnan, Marian, De Craen, Anton J. M., Suchiman, H. Eka D., Hofman, Albert, Oostra, Ben, Uitterlinden, Andre G., Willemsen, Gonneke, Plattee, Mathieu, Veldink, Jan H., Van den Berg, Leonard H., Pitts, Steven J., Potluri, Shobha, Sundar, Purnima, Cox, David R., Sunyaev, Shamil R., Den Dunnen, Johan T., Stoneking, Mark, De Knijff, Peter, Kayser, Manfred, Li, Qibin, Li, Yingrui, Du, Yuanping, Chen, Ruoyan, Cao, Hongzhi, Li, Ning, Cao, Sujie, Wang, Jun, Bovenberg, Jasper A., Peer, Itsik, Slagboom, P. Eline, Van Duijn, Cornelia M., Boomsma, Dorret I., Van Ommen, Gert-Jan B., De Bakker, Paul I. W., Swertz, Morris A., Wijmenga, Cisca, Francioli, Laurent C., Menelaou, Andronild, Pulit, Sara L., Van Dijk, Freerk, Palamara, Pier Francesco, Elbers, Clara C., Neerincx, Pieter B. T., Ye, Kai, Guryev, Victor, Kloosterman, Wigard P., Deelen, Patrick, Abdellaoui, Abdel, Van Leeuwen, Elisabeth M., Van Oven, Mannis, Vermaat, Martijn, Li, Mingkun, Laros, Jeroen F. J., Karssen, Lennart C., Kanterakis, Alexandros, Amin, Najaf, Hottenga, Jouke Jan, Lameijer, Eric-Wubbo, Kattenberg, Mathijs, Dijkstra, Martijn, Byelas, Heorhiy, Van Settenl, Jessica, Van Schaik, Barbera D. C., Bot, Jan, Nijman, Isaac J., Renkens, Ivo, Marscha, Tobias, Schonhuth, Alexander, Hehir-Kwa, Jayne Y., Handsaker, Robert E., Polak, Paz, Sohail, Mashaal, Vuzman, Dana, Hormozdiari, Fereydoun, Van Enckevort, David, Mei, Hailiang, Koval, Vyacheslav, Moed, Ma-Tthijs H., Van der Velde, K. Joeri, Rivadeneira, Fernando, Estrada, Karol, Medina-Gomez, Carolina, Isaacs, Aaron, McCarroll, Steven A., Beekrnan, Marian, De Craen, Anton J. M., Suchiman, H. Eka D., Hofman, Albert, Oostra, Ben, Uitterlinden, Andre G., Willemsen, Gonneke, Plattee, Mathieu, Veldink, Jan H., Van den Berg, Leonard H., Pitts, Steven J., Potluri, Shobha, Sundar, Purnima, Cox, David R., Sunyaev, Shamil R., Den Dunnen, Johan T., Stoneking, Mark, De Knijff, Peter, Kayser, Manfred, Li, Qibin, Li, Yingrui, Du, Yuanping, Chen, Ruoyan, Cao, Hongzhi, Li, Ning, Cao, Sujie, Wang, Jun, Bovenberg, Jasper A., Peer, Itsik, Slagboom, P. Eline, Van Duijn, Cornelia M., Boomsma, Dorret I., Van Ommen, Gert-Jan B., De Bakker, Paul I. W., Swertz, Morris A., and Wijmenga, Cisca

Published
2014

48. The Genome of the Netherlands: design, and project goals

Author

Boomsma, Dorret I, primary, Wijmenga, Cisca, additional, Slagboom, Eline P, additional, Swertz, Morris A, additional, Karssen, Lennart C, additional, Abdellaoui, Abdel, additional, Ye, Kai, additional, Guryev, Victor, additional, Vermaat, Martijn, additional, van Dijk, Freerk, additional, Francioli, Laurent C, additional, Hottenga, Jouke Jan, additional, Laros, Jeroen F J, additional, Li, Qibin, additional, Li, Yingrui, additional, Cao, Hongzhi, additional, Chen, Ruoyan, additional, Du, Yuanping, additional, Li, Ning, additional, Cao, Sujie, additional, van Setten, Jessica, additional, Menelaou, Androniki, additional, Pulit, Sara L, additional, Hehir-Kwa, Jayne Y, additional, Beekman, Marian, additional, Elbers, Clara C, additional, Byelas, Heorhiy, additional, de Craen, Anton J M, additional, Deelen, Patrick, additional, Dijkstra, Martijn, additional, den Dunnen, Johan T, additional, de Knijff, Peter, additional, Houwing-Duistermaat, Jeanine, additional, Koval, Vyacheslav, additional, Estrada, Karol, additional, Hofman, Albert, additional, Kanterakis, Alexandros, additional, Enckevort, David van, additional, Mai, Hailiang, additional, Kattenberg, Mathijs, additional, van Leeuwen, Elisabeth M, additional, Neerincx, Pieter B T, additional, Oostra, Ben, additional, Rivadeneira, Fernanodo, additional, Suchiman, Eka H D, additional, Uitterlinden, Andre G, additional, Willemsen, Gonneke, additional, Wolffenbuttel, Bruce H, additional, Wang, Jun, additional, de Bakker, Paul I W, additional, van Ommen, Gert-Jan, additional, and van Duijn, Cornelia M, additional

Published
2013
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49. A framework for the detection of de novo mutations in family-based sequencing data

Author

Francioli, Laurent C, Cretu-Stancu, Mircea, Garimella, Kiran V, Fromer, Menachem, Kloosterman, Wigard P, Samocha, Kaitlin E, Neale, Benjamin M, Daly, Mark J, Banks, Eric, DePristo, Mark A, and de Bakker, Paul IW

Abstract

Germline mutation detection from human DNA sequence data is challenging due to the rarity of such events relative to the intrinsic error rates of sequencing technologies and the uneven coverage across the genome. We developed PhaseByTransmission (PBT) to identify de novo single nucleotide variants and short insertions and deletions (indels) from sequence data collected in parent-offspring trios. We compute the joint probability of the data given the genotype likelihoods in the individual family members, the known familial relationships and a prior probability for the mutation rate. Candidate de novo mutations (DNMs) are reported along with their posterior probability, providing a systematic way to prioritize them for validation. Our tool is integrated in the Genome Analysis Toolkit and can be used together with the ReadBackedPhasing module to infer the parental origin of DNMs based on phase-informative reads. Using simulated data, we show that PBT outperforms existing tools, especially in low coverage data and on the X chromosome. We further show that PBT displays high validation rates on empirical parent-offspring sequencing data for whole-exome data from 104 trios and X-chromosome data from 249 parent-offspring families. Finally, we demonstrate an association between father’s age at conception and the number of DNMs in female offspring’s X chromosome, consistent with previous literature reports.

Published
2017
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50. 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., and Kosmicki, Jack A.

Published
2021
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