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1. Correction: Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population.

Author

Manuel A Rivas, Brandon E Avila, Jukka Koskela, Hailiang Huang, Christine Stevens, Matti Pirinen, Talin Haritunians, Benjamin M Neale, Mitja Kurki, Andrea Ganna, Daniel Graham, Benjamin Glaser, Inga Peter, Gil Atzmon, Nir Barzilai, Adam P Levine, Elena Schiff, Nikolas Pontikos, Ben Weisburd, Monkol Lek, Konrad J Karczewski, Jonathan Bloom, Eric V Minikel, Britt-Sabina Petersen, Laurent Beaugerie, Philippe Seksik, Jacques Cosnes, Stefan Schreiber, Bernd Bokemeyer, Johannes Bethge, International IBD Genetics Consortium, NIDDK IBD Genetics Consortium, T2D-GENES Consortium, Graham Heap, Tariq Ahmad, Vincent Plagnol, Anthony W Segal, Stephan Targan, Dan Turner, Paivi Saavalainen, Martti Farkkila, Kimmo Kontula, Aarno Palotie, Steven R Brant, Richard H Duerr, Mark S Silverberg, John D Rioux, Rinse K Weersma, Andre Franke, Luke Jostins, Carl A Anderson, Jeffrey C Barrett, Daniel G MacArthur, Chaim Jalas, Harry Sokol, Ramnik J Xavier, Ann Pulver, Judy H Cho, Dermot P B McGovern, and Mark J Daly

Subjects
Genetics, QH426-470
Abstract

[This corrects the article DOI: 10.1371/journal.pgen.1007329.].

Published
2019
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2. Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population.

Author

Manuel A Rivas, Brandon E Avila, Jukka Koskela, Hailiang Huang, Christine Stevens, Matti Pirinen, Talin Haritunians, Benjamin M Neale, Mitja Kurki, Andrea Ganna, Daniel Graham, Benjamin Glaser, Inga Peter, Gil Atzmon, Nir Barzilai, Adam P Levine, Elena Schiff, Nikolas Pontikos, Ben Weisburd, Monkol Lek, Konrad J Karczewski, Jonathan Bloom, Eric V Minikel, Britt-Sabina Petersen, Laurent Beaugerie, Philippe Seksik, Jacques Cosnes, Stefan Schreiber, Bernd Bokemeyer, Johannes Bethge, International IBD Genetics Consortium, NIDDK IBD Genetics Consortium, T2D-GENES Consortium, Graham Heap, Tariq Ahmad, Vincent Plagnol, Anthony W Segal, Stephan Targan, Dan Turner, Paivi Saavalainen, Martti Farkkila, Kimmo Kontula, Aarno Palotie, Steven R Brant, Richard H Duerr, Mark S Silverberg, John D Rioux, Rinse K Weersma, Andre Franke, Luke Jostins, Carl A Anderson, Jeffrey C Barrett, Daniel G MacArthur, Chaim Jalas, Harry Sokol, Ramnik J Xavier, Ann Pulver, Judy H Cho, Dermot P B McGovern, and Mark J Daly

Subjects
Genetics, QH426-470
Abstract

As part of a broader collaborative network of exome sequencing studies, we developed a jointly called data set of 5,685 Ashkenazi Jewish exomes. We make publicly available a resource of site and allele frequencies, which should serve as a reference for medical genetics in the Ashkenazim (hosted in part at https://ibd.broadinstitute.org, also available in gnomAD at http://gnomad.broadinstitute.org). We estimate that 34% of protein-coding alleles present in the Ashkenazi Jewish population at frequencies greater than 0.2% are significantly more frequent (mean 15-fold) than their maximum frequency observed in other reference populations. Arising via a well-described founder effect approximately 30 generations ago, this catalog of enriched alleles can contribute to differences in genetic risk and overall prevalence of diseases between populations. As validation we document 148 AJ enriched protein-altering alleles that overlap with "pathogenic" ClinVar alleles (table available at https://github.com/macarthur-lab/clinvar/blob/master/output/clinvar.tsv), including those that account for 10-100 fold differences in prevalence between AJ and non-AJ populations of some rare diseases, especially recessive conditions, including Gaucher disease (GBA, p.Asn409Ser, 8-fold enrichment); Canavan disease (ASPA, p.Glu285Ala, 12-fold enrichment); and Tay-Sachs disease (HEXA, c.1421+1G>C, 27-fold enrichment; p.Tyr427IlefsTer5, 12-fold enrichment). We next sought to use this catalog, of well-established relevance to Mendelian disease, to explore Crohn's disease, a common disease with an estimated two to four-fold excess prevalence in AJ. We specifically attempt to evaluate whether strong acting rare alleles, particularly protein-truncating or otherwise large effect-size alleles, enriched by the same founder-effect, contribute excess genetic risk to Crohn's disease in AJ, and find that ten rare genetic risk factors in NOD2 and LRRK2 are enriched in AJ (p < 0.005), including several novel contributing alleles, show evidence of association to CD. Independently, we find that genomewide common variant risk defined by GWAS shows a strong difference between AJ and non-AJ European control population samples (0.97 s.d. higher, p

Published
2018
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3. A structural variation reference for medical and population genetics.

Author

Ryan L. Collins, Harrison Brand, Konrad J. Karczewski, Xuefang Zhao, Jessica Alföldi, Laurent C. Francioli, Amit V. Khera, Chelsea Lowther, Laura D. Gauthier, Harold Wang, Nicholas A. Watts, Matthew Solomonson, Alexander Baumann, Ruchi Munshi, Mark Walker, Christopher W. Whelan, Yongqing Huang, Ted Brookings, Ted Sharpe, Matthew R. Stone, Elise Valkanas, Jack Fu, Grace Tiao, Kristen M. Laricchia, Valentín Ruano-Rubio, Christine Stevens, Namrata Gupta, Caroline Cusick, Lauren Margolin, Irina M. Armean, Eric Banks, Louis Bergelson, Kristian Cibulskis, Kristen M. Connolly, Miguel Covarrubias, Beryl B. Cummings, Mark J. Daly, Stacey Donnelly, Yossi Farjoun, Steven Ferriera, Stacey Gabriel, Jeff Gentry, Thibault Jeandet, Diane Kaplan, Christopher Llanwarne, Eric V. Minikel, Benjamin M. Neale, Sam Novod, Anne H. O'Donnell-Luria, Nikelle Petrillo, Timothy Poterba, David Roazen, Andrea Saltzman, Kaitlin E. Samocha, Molly Schleicher, Cotton Seed, José Soto, Kathleen Tibbetts, Charlotte Tolonen, Christopher Vittal, Gordon Wade, Arcturus Wang, Qingbo Wang, James S. Ware, Ben Weisburd, Nicola Whiffin, Carlos A. Aguilar Salinas, Tariq Ahmad 0003, Christine M. Albert, Diego Ardissino, Gil Atzmon, John Barnard, Laurent Beaugerie, Emelia J. Benjamin, Michael Boehnke, Lori L. Bonnycastle, Erwin P. Bottinger, Donald W. Bowden, Matthew J. Bown, John C. Chambers, Juliana C. Chan, Daniel Chasman, Judy Cho, Mina K. Chung, Bruce Cohen, Adolfo Correa, Dana Dabelea, Dawood Darbar, Ravindranath Duggirala, Josée Dupuis, Patrick T. Ellinor, Roberto Elosua, Jeanette Erdmann, Tõnu Esko, Martti Färkkilä, Jose Florez, Andre Franke, Gad Getz, Benjamin Glaser, Stephen J. Glatt, David Goldstein, Clicerio Gonzalez, Leif Groop, Christopher A. Haiman, Craig Hanis, Matthew Harms, Mikko Hiltunen, Matti M. Holi, Christina M. Hultman, Mikko Kallela, Jaakko Kaprio, Sekar Kathiresan, Bong-Jo Kim, Young Jin Kim, George Kirov, Jaspal Kooner, Seppo Koskinen, Harlan M. Krumholz, Subra Kugathasan, Soo Heon Kwak, Markku Laakso, Terho Lehtimäki, Ruth J. F. Loos, Steven A. Lubitz, Ronald C. W. Ma, Daniel G. MacArthur, Jaume Marrugat, Kari M. Mattila, Steven A. McCarroll, Mark I. McCarthy, Dermot McGovern, Ruth McPherson, James B. Meigs, Olle Melander, Andres Metspalu, Peter M. Nilsson, Michael C. O'Donovan, Dost öngür, Lorena Orozco, Michael J. Owen, Colin N. A. Palmer, Aarno Palotie, Kyong Soo Park, Carlos Pato, Ann E. Pulver, Nazneen Rahman, Anne M. Remes, John D. Rioux, Samuli Ripatti, Dan M. Roden, Danish Saleheen, Veikko Salomaa, Nilesh J. Samani, Jeremiah Scharf, Heribert Schunkert, Moore B. Shoemaker, Pamela Sklar, Hilkka Soininen, Harry Sokol, Tim Spector, Patrick F. Sullivan, Jaana Suvisaari, E. Shyong Tai, Yik Ying Teo, Tuomi Tiinamaija, Ming Tsuang, Dan Turner, Teresa Tusie-Luna, Erkki Vartiainen, Hugh Watkins, Rinse K. Weersma, Maija Wessman, James G. Wilson, Ramnik J. Xavier, Kent D. Taylor, Henry J. Lin, Stephen S. Rich, Wendy S. Post, Yii-Der Ida Chen, Jerome I. Rotter, Chad Nusbaum, Anthony A. Philippakis, Eric S. Lander, and Michael E. Talkowski

Published
2020
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4. ClinVar data parsing [version 1; referees: 2 approved]

Author

Xiaolei Zhang, Eric V. Minikel, Anne H. O'Donnell-Luria, Daniel G. MacArthur, James S. Ware, and Ben Weisburd

Subjects
Bioinformatics, Genomics, Medicine, Science
Abstract

This software repository provides a pipeline for converting raw ClinVar data files into analysis-friendly tab-delimited tables, and also provides these tables for the most recent ClinVar release. Separate tables are generated for genome builds GRCh37 and GRCh38 as well as for mono-allelic variants and complex multi-allelic variants. Additionally, the tables are augmented with allele frequencies from the ExAC and gnomAD datasets as these are often consulted when analyzing ClinVar variants. Overall, this work provides ClinVar data in a format that is easier to work with and can be directly loaded into a variety of popular analysis tools such as R, python pandas, and SQL databases.

Published
2017
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5. The effect of LRRK2 loss-of-function variants in humans

Author

Nicola, Whiffin, Irina M, Armean, Aaron, Kleinman, Jamie L, Marshall, Eric V, Minikel, Julia K, Goodrich, Nicholas M, Quaife, Joanne B, Cole, Qingbo, Wang, Konrad J, Karczewski, Beryl B, Cummings, Laurent, Francioli, Kristen, Laricchia, Anna, Guan, Babak, Alipanahi, Peter, Morrison, Marco A S, Baptista, Kalpana M, Merchant, James S, Ware, Aki S, Havulinna, Bozenna, Iliadou, Jung-Jin, Lee, Girish N, Nadkarni, Cole, Whiteman, Mark, Daly, Tõnu, Esko, Christina, Hultman, Ruth J F, Loos, Lili, Milani, Aarno, Palotie, Carlos, Pato, Michele, Pato, Danish, Saleheen, Patrick F, Sullivan, Jessica, Alföldi, Paul, Cannon, and Catherine H, Wilson

Subjects
Adult, Aged, 80 and over, Male, Heterozygote, Longevity, Parkinson Disease, Middle Aged, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Cell Line, Phenotype, Loss of Function Mutation, Gain of Function Mutation, Humans, Female, Myocytes, Cardiac, Lymphocytes, Author Correction, Embryonic Stem Cells, Aged, Biological Specimen Banks
Abstract

Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes

Published
2020

6. Pathogenic ASXL1 somatic variants in reference databases complicate germline variant interpretation for Bohring-Opitz Syndrome

Author

Colleen M, Carlston, Anne H, O'Donnell-Luria, Hunter R, Underhill, Beryl B, Cummings, Ben, Weisburd, Eric V, Minikel, Daniel P, Birnbaum, Tatiana, Tvrdik, Daniel G, MacArthur, and Rong, Mao

Subjects
Aged, 80 and over, Male, Facies, Infant, Middle Aged, Repressor Proteins, Craniosynostoses, Phenotype, Amino Acid Substitution, Child, Preschool, Intellectual Disability, Databases, Genetic, Mutation, Humans, Female, Alleles, Genetic Association Studies, Germ-Line Mutation, Aged
Abstract

The clinical interpretation of genetic variants has come to rely heavily on reference population databases such as the Exome Aggregation Consortium (ExAC) database. Pathogenic variants in genes associated with severe, pediatric-onset, highly penetrant, autosomal dominant conditions are assumed to be absent or rare in these databases. Exome sequencing of a 6-year-old female patient with seizures, developmental delay, dysmorphic features, and failure to thrive identified an ASXL1 variant previously reported as causative of Bohring-Opitz syndrome (BOS). Surprisingly, the variant was observed seven times in the ExAC database, presumably in individuals without BOS. Although the BOS phenotype fit, the presence of the variant in reference population databases introduced ambiguity in result interpretation. Review of the literature revealed that acquired somatic mosaicism of ASXL1 variants (including pathogenic variants) during hematopoietic clonal expansion can occur with aging in healthy individuals. We examined all ASXL1 truncating variants in the ExAC database and determined most are likely somatic. Failure to consider somatic mosaicism may lead to the inaccurate assumption that conditions like BOS have reduced penetrance, or the misclassification of potentially pathogenic variants.

Published
2016

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