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2. Regulation of autism-relevant behaviors by cerebellar–prefrontal cortical circuits

Author

Kelly, Elyza, Meng, Fantao, Fujita, Hirofumi, Morgado, Felipe, Kazemi, Yasaman, Rice, Laura C, Ren, Chongyu, Escamilla, Christine Ochoa, Gibson, Jennifer M, Sajadi, Sanaz, Pendry, Robert J, Tan, Tommy, Ellegood, Jacob, Basson, M Albert, Blakely, Randy D, Dindot, Scott V, Golzio, Christelle, Hahn, Maureen K, Katsanis, Nicholas, Robins, Diane M, Silverman, Jill L, Singh, Karun K, Wevrick, Rachel, Taylor, Margot J, Hammill, Christopher, Anagnostou, Evdokia, Pfeiffer, Brad E, Stoodley, Catherine J, Lerch, Jason P, du Lac, Sascha, and Tsai, Peter T

Subjects
Mental Health, Intellectual and Developmental Disabilities (IDD), Autism, Pediatric, Neurosciences, Brain Disorders, Basic Behavioral and Social Science, Behavioral and Social Science, Aetiology, 2.1 Biological and endogenous factors, Underpinning research, 1.1 Normal biological development and functioning, Mental health, Animals, Autism Spectrum Disorder, Cerebellum, Male, Mice, Mice, Mutant Strains, Neural Pathways, Prefrontal Cortex, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Cerebellar dysfunction has been demonstrated in autism spectrum disorders (ASDs); however, the circuits underlying cerebellar contributions to ASD-relevant behaviors remain unknown. In this study, we demonstrated functional connectivity between the cerebellum and the medial prefrontal cortex (mPFC) in mice; showed that the mPFC mediates cerebellum-regulated social and repetitive/inflexible behaviors; and showed disruptions in connectivity between these regions in multiple mouse models of ASD-linked genes and in individuals with ASD. We delineated a circuit from cerebellar cortical areas Right crus 1 (Rcrus1) and posterior vermis through the cerebellar nuclei and ventromedial thalamus and culminating in the mPFC. Modulation of this circuit induced social deficits and repetitive behaviors, whereas activation of Purkinje cells (PCs) in Rcrus1 and posterior vermis improved social preference impairments and repetitive/inflexible behaviors, respectively, in male PC-Tsc1 mutant mice. These data raise the possibility that these circuits might provide neuromodulatory targets for the treatment of ASD.

Published
2020

3. Mutations in the Kinesin-2 Motor KIF3B Cause an Autosomal-Dominant Ciliopathy.

Author

Cogné, Benjamin, Latypova, Xenia, Senaratne, Lokuliyanage Dona Samudita, Martin, Ludovic, Koboldt, Daniel C, Kellaris, Georgios, Fievet, Lorraine, Le Meur, Guylène, Caldari, Dominique, Debray, Dominique, Nizon, Mathilde, Frengen, Eirik, Bowne, Sara J, 99 Lives Consortium, Cadena, Elizabeth L, Daiger, Stephen P, Bujakowska, Kinga M, Pierce, Eric A, Gorin, Michael, Katsanis, Nicholas, Bézieau, Stéphane, Petersen-Jones, Simon M, Occelli, Laurence M, Lyons, Leslie A, Legeai-Mallet, Laurence, Sullivan, Lori S, Davis, Erica E, and Isidor, Bertrand

Subjects
Lives Consortium, Retina, Cilia, Animals, Zebrafish, Cats, Humans, Rhodopsin, Pedigree, Amino Acid Sequence, Larva, Heterozygote, Genes, Dominant, Phenotype, Mutation, Middle Aged, Child, Preschool, Female, Male, Photoreceptor Cells, Genome-Wide Association Study, Young Adult, Ciliopathies, Kinesins, KIF3B, feline genetics, hepatic fibrosis, kinesin, primary cilia, retinopathy, whole-exome sequencing, zebrafish, Neurosciences, Clinical Research, Genetics, Pediatric, Polycystic Kidney Disease, Eye Disease and Disorders of Vision, Congenital Structural Anomalies, Neurodegenerative, Kidney Disease, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Eye, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Kinesin-2 enables ciliary assembly and maintenance as an anterograde intraflagellar transport (IFT) motor. Molecular motor activity is driven by a heterotrimeric complex comprised of KIF3A and KIF3B or KIF3C plus one non-motor subunit, KIFAP3. Using exome sequencing, we identified heterozygous KIF3B variants in two unrelated families with hallmark ciliopathy phenotypes. In the first family, the proband presents with hepatic fibrosis, retinitis pigmentosa, and postaxial polydactyly; he harbors a de novo c.748G>C (p.Glu250Gln) variant affecting the kinesin motor domain encoded by KIF3B. The second family is a six-generation pedigree affected predominantly by retinitis pigmentosa. Affected individuals carry a heterozygous c.1568T>C (p.Leu523Pro) KIF3B variant segregating in an autosomal-dominant pattern. We observed a significant increase in primary cilia length in vitro in the context of either of the two mutations while variant KIF3B proteins retained stability indistinguishable from wild type. Furthermore, we tested the effects of KIF3B mutant mRNA expression in the developing zebrafish retina. In the presence of either missense variant, rhodopsin was sequestered to the photoreceptor rod inner segment layer with a concomitant increase in photoreceptor cilia length. Notably, impaired rhodopsin trafficking is also characteristic of recessive KIF3B models as exemplified by an early-onset, autosomal-recessive, progressive retinal degeneration in Bengal cats; we identified a c.1000G>A (p.Ala334Thr) KIF3B variant by genome-wide association study and whole-genome sequencing. Together, our genetic, cell-based, and in vivo modeling data delineate an autosomal-dominant syndromic retinal ciliopathy in humans and suggest that multiple KIF3B pathomechanisms can impair kinesin-driven ciliary transport in the photoreceptor.

Published
2020

4. Meta-analysis fine-mapping is often miscalibrated at single-variant resolution

Author

Zhou, Wei, Kanai, Masahiro, Wu, Kuan-Han H., Rasheed, Humaira, Tsuo, Kristin, Hirbo, Jibril B., Wang, Ying, Bhattacharya, Arjun, Zhao, Huiling, Namba, Shinichi, Surakka, Ida, Wolford, Brooke N., Lo Faro, Valeria, Lopera-Maya, Esteban A., Läll, Kristi, Favé, Marie-Julie, Partanen, Juulia J., Chapman, Sinéad B., Karjalainen, Juha, Kurki, Mitja, Maasha, Mutaamba, Brumpton, Ben M., Chavan, Sameer, Chen, Tzu-Ting, Daya, Michelle, Ding, Yi, Feng, Yen-Chen A., Guare, Lindsay A., Gignoux, Christopher R., Graham, Sarah E., Hornsby, Whitney E., Ingold, Nathan, Ismail, Said I., Johnson, Ruth, Laisk, Triin, Lin, Kuang, Lv, Jun, Millwood, Iona Y., Moreno-Grau, Sonia, Nam, Kisung, Palta, Priit, Pandit, Anita, Preuss, Michael H., Saad, Chadi, Setia-Verma, Shefali, Thorsteinsdottir, Unnur, Uzunovic, Jasmina, Verma, Anurag, Zawistowski, Matthew, Zhong, Xue, Afifi, Nahla, Al-Dabhani, Kawthar M., Al Thani, Asma, Bradford, Yuki, Campbell, Archie, Crooks, Kristy, de Bock, Geertruida H., Damrauer, Scott M., Douville, Nicholas J., Finer, Sarah, Fritsche, Lars G., Fthenou, Eleni, Gonzalez-Arroyo, Gilberto, Griffiths, Christopher J., Guo, Yu, Hunt, Karen A., Ioannidis, Alexander, Jansonius, Nomdo M., Konuma, Takahiro, Michael Lee, Ming Ta, Lopez-Pineda, Arturo, Matsuda, Yuta, Marioni, Riccardo E., Moatamed, Babak, Nava-Aguilar, Marco A., Numakura, Kensuke, Patil, Snehal, Rafaels, Nicholas, Richmond, Anne, Rojas-Muñoz, Agustin, Shortt, Jonathan A., Straub, Peter, Tao, Ran, Vanderwerff, Brett, Vernekar, Manvi, Veturi, Yogasudha, Barnes, Kathleen C., Boezen, Marike, Chen, Zhengming, Chen, Chia-Yen, Cho, Judy, Smith, George Davey, Finucane, Hilary K., Franke, Lude, Gamazon, Eric R., Ganna, Andrea, Gaunt, Tom R., Ge, Tian, Huang, Hailiang, Huffman, Jennifer, Katsanis, Nicholas, Koskela, Jukka T., Lajonchere, Clara, Law, Matthew H., Li, Liming, Lindgren, Cecilia M., Loos, Ruth J.F., MacGregor, Stuart, Matsuda, Koichi, Olsen, Catherine M., Porteous, David J., Shavit, Jordan A., Snieder, Harold, Takano, Tomohiro, Trembath, Richard C., Vonk, Judith M., Whiteman, David C., Wicks, Stephen J., Wijmenga, Cisca, Wright, John, Zheng, Jie, Zhou, Xiang, Awadalla, Philip, Boehnke, Michael, Bustamante, Carlos D., Cox, Nancy J., Fatumo, Segun, Geschwind, Daniel H., Hayward, Caroline, Hveem, Kristian, Kenny, Eimear E., Lee, Seunggeun, Lin, Yen-Feng, Mbarek, Hamdi, Mägi, Reedik, Martin, Hilary C., Medland, Sarah E., Okada, Yukinori, Palotie, Aarno V., Pasaniuc, Bogdan, Rader, Daniel J., Ritchie, Marylyn D., Sanna, Serena, Smoller, Jordan W., Stefansson, Kari, van Heel, David A., Walters, Robin G., Zöllner, Sebastian, Biobank of the Americas, Biobank Japan Project, BioMe, BioVU, CanPath - Ontario Health Study, China Kadoorie Biobank Collaborative Group, Colorado Center for Personalized Medicine, deCODE Genetics, Estonian Biobank, FinnGen, Generation Scotland, Genes & Health Research Team, LifeLines, Mass General Brigham Biobank, Michigan Genomics Initiative, National Biobank of Korea, Penn Medicine BioBank, Qatar Biobank, The Qskin Sun and Health Study, Taiwan Biobank, The Hunt Study, Ucla Atlas Community Health Initiative, Uganda Genome Resource, Uk Biobank, Martin, Alicia R., Willer, Cristen J., Daly, Mark J., Neale, Benjamin M., and Elzur, Roy

Published
2022
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5. Global Biobank Meta-analysis Initiative: Powering genetic discovery across human disease

Author

Zhou, Wei, Kanai, Masahiro, Wu, Kuan-Han H., Rasheed, Humaira, Tsuo, Kristin, Hirbo, Jibril B., Wang, Ying, Bhattacharya, Arjun, Zhao, Huiling, Namba, Shinichi, Surakka, Ida, Wolford, Brooke N., Lo Faro, Valeria, Lopera-Maya, Esteban A., Läll, Kristi, Favé, Marie-Julie, Partanen, Juulia J., Chapman, Sinéad B., Karjalainen, Juha, Kurki, Mitja, Maasha, Mutaamba, Brumpton, Ben M., Chavan, Sameer, Chen, Tzu-Ting, Daya, Michelle, Ding, Yi, Feng, Yen-Chen A., Guare, Lindsay A., Gignoux, Christopher R., Graham, Sarah E., Hornsby, Whitney E., Ingold, Nathan, Ismail, Said I., Johnson, Ruth, Laisk, Triin, Lin, Kuang, Lv, Jun, Millwood, Iona Y., Moreno-Grau, Sonia, Nam, Kisung, Palta, Priit, Pandit, Anita, Preuss, Michael H., Saad, Chadi, Setia-Verma, Shefali, Thorsteinsdottir, Unnur, Uzunovic, Jasmina, Verma, Anurag, Zawistowski, Matthew, Zhong, Xue, Afifi, Nahla, Al-Dabhani, Kawthar M., Al Thani, Asma, Bradford, Yuki, Campbell, Archie, Crooks, Kristy, de Bock, Geertruida H., Damrauer, Scott M., Douville, Nicholas J., Finer, Sarah, Fritsche, Lars G., Fthenou, Eleni, Gonzalez-Arroyo, Gilberto, Griffiths, Christopher J., Guo, Yu, Hunt, Karen A., Ioannidis, Alexander, Jansonius, Nomdo M., Konuma, Takahiro, Lee, Ming Ta Michael, Lopez-Pineda, Arturo, Matsuda, Yuta, Marioni, Riccardo E., Moatamed, Babak, Nava-Aguilar, Marco A., Numakura, Kensuke, Patil, Snehal, Rafaels, Nicholas, Richmond, Anne, Rojas-Muñoz, Agustin, Shortt, Jonathan A., Straub, Peter, Tao, Ran, Vanderwerff, Brett, Vernekar, Manvi, Veturi, Yogasudha, Barnes, Kathleen C., Boezen, Marike, Chen, Zhengming, Chen, Chia-Yen, Cho, Judy, Smith, George Davey, Finucane, Hilary K., Franke, Lude, Gamazon, Eric R., Ganna, Andrea, Gaunt, Tom R., Ge, Tian, Huang, Hailiang, Huffman, Jennifer, Katsanis, Nicholas, Koskela, Jukka T., Lajonchere, Clara, Law, Matthew H., Li, Liming, Lindgren, Cecilia M., Loos, Ruth J.F., MacGregor, Stuart, Matsuda, Koichi, Olsen, Catherine M., Porteous, David J., Shavit, Jordan A., Snieder, Harold, Takano, Tomohiro, Trembath, Richard C., Vonk, Judith M., Whiteman, David C., Wicks, Stephen J., Wijmenga, Cisca, Wright, John, Zheng, Jie, Zhou, Xiang, Awadalla, Philip, Boehnke, Michael, Bustamante, Carlos D., Cox, Nancy J., Fatumo, Segun, Geschwind, Daniel H., Hayward, Caroline, Hveem, Kristian, Kenny, Eimear E., Lee, Seunggeun, Lin, Yen-Feng, Mbarek, Hamdi, Mägi, Reedik, Martin, Hilary C., Medland, Sarah E., Okada, Yukinori, Palotie, Aarno V., Pasaniuc, Bogdan, Rader, Daniel J., Ritchie, Marylyn D., Sanna, Serena, Smoller, Jordan W., Stefansson, Kari, van Heel, David A., Walters, Robin G., Zöllner, Sebastian, Martin, Alicia R., Willer, Cristen J., Daly, Mark J., and Neale, Benjamin M.

Published
2022
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6. Performance of computational methods for the evaluation of pericentriolar material 1 missense variants in CAGI‐5

Author

Monzon, Alexander Miguel, Carraro, Marco, Chiricosta, Luigi, Reggiani, Francesco, Han, James, Ozturk, Kivilcim, Wang, Yanran, Miller, Maximilian, Bromberg, Yana, Capriotti, Emidio, Savojardo, Castrense, Babbi, Giulia, Martelli, Pier L, Casadio, Rita, Katsonis, Panagiotis, Lichtarge, Olivier, Carter, Hannah, Kousi, Maria, Katsanis, Nicholas, Andreoletti, Gaia, Moult, John, Brenner, Steven E, Ferrari, Carlo, Leonardi, Emanuela, and Tosatto, Silvio CE

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Schizophrenia, Genetics, Brain Disorders, Mental Health, Aetiology, 2.1 Biological and endogenous factors, Mental health, Autoantigens, Cell Cycle Proteins, Computational Biology, Databases, Genetic, Genetic Predisposition to Disease, Humans, Mutation, Missense, Neural Networks, Computer, Phenotype, Polymorphism, Single Nucleotide, bioinformatics tools, community challenge, critical assessment, effect prediction, missense mutations, variant interpretation, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

The CAGI-5 pericentriolar material 1 (PCM1) challenge aimed to predict the effect of 38 transgenic human missense mutations in the PCM1 protein implicated in schizophrenia. Participants were provided with 16 benign variants (negative controls), 10 hypomorphic, and 12 loss of function variants. Six groups participated and were asked to predict the probability of effect and standard deviation associated to each mutation. Here, we present the challenge assessment. Prediction performance was evaluated using different measures to conclude in a final ranking which highlights the strengths and weaknesses of each group. The results show a great variety of predictions where some methods performed significantly better than others. Benign variants played an important role as negative controls, highlighting predictors biased to identify disease phenotypes. The best predictor, Bromberg lab, used a neural-network-based method able to discriminate between neutral and non-neutral single nucleotide polymorphisms. The CAGI-5 PCM1 challenge allowed us to evaluate the state of the art techniques for interpreting the effect of novel variants for a difficult target protein.

Published
2019

7. Oligogenic Effects of 16p11.2 Copy-Number Variation on Craniofacial Development

Author

Qiu, Yuqi, Arbogast, Thomas, Lorenzo, Sandra Martin, Li, Hongying, Tang, Shih C, Richardson, Ellen, Hong, Oanh, Cho, Shawn, Shanta, Omar, Pang, Timothy, Corsello, Christina, Deutsch, Curtis K, Chevalier, Claire, Davis, Erica E, Iakoucheva, Lilia M, Herault, Yann, Katsanis, Nicholas, Messer, Karen, and Sebat, Jonathan

Subjects
Clinical Research, Mental Health, Dental/Oral and Craniofacial Disease, Genetics, Pediatric, Human Genome, Congenital Structural Anomalies, Brain Disorders, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Autistic Disorder, Chromosome Deletion, Chromosome Disorders, Chromosomes, Human, Pair 16, Craniofacial Abnormalities, DNA Copy Number Variations, Female, Humans, Intellectual Disability, Male, Biochemistry and Cell Biology, Medical Physiology
Abstract

A copy-number variant (CNV) of 16p11.2 encompassing 30 genes is associated with developmental and psychiatric disorders, head size, and body mass. The genetic mechanisms that underlie these associations are not understood. To determine the influence of 16p11.2 genes on development, we investigated the effects of CNV on craniofacial structure in humans and model organisms. We show that deletion and duplication of 16p11.2 have "mirror" effects on specific craniofacial features that are conserved between human and rodent models of the CNV. By testing dosage effects of individual genes on the shape of the mandible in zebrafish, we identify seven genes with significant effects individually and find evidence for others when genes were tested in combination. The craniofacial phenotypes of 16p11.2 CNVs represent a model for studying the effects of genes on development, and our results suggest that the associated facial gestalts are attributable to the combined effects of multiple genes.

Published
2019

8. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

Author

Helbig, Katherine L, Lauerer, Robert J, Bahr, Jacqueline C, Souza, Ivana A, Myers, Candace T, Uysal, Betül, Schwarz, Niklas, Gandini, Maria A, Huang, Sun, Keren, Boris, Mignot, Cyril, Afenjar, Alexandra, de Villemeur, Thierry Billette, Héron, Delphine, Nava, Caroline, Valence, Stéphanie, Buratti, Julien, Fagerberg, Christina R, Soerensen, Kristina P, Kibaek, Maria, Kamsteeg, Erik-Jan, Koolen, David A, Gunning, Boudewijn, Schelhaas, H Jurgen, Kruer, Michael C, Fox, Jordana, Bakhtiari, Somayeh, Jarrar, Randa, Padilla-Lopez, Sergio, Lindstrom, Kristin, Jin, Sheng Chih, Zeng, Xue, Bilguvar, Kaya, Papavasileiou, Antigone, Xing, Qinghe, Zhu, Changlian, Boysen, Katja, Vairo, Filippo, Lanpher, Brendan C, Klee, Eric W, Tillema, Jan-Mendelt, Payne, Eric T, Cousin, Margot A, Kruisselbrink, Teresa M, Wick, Myra J, Baker, Joshua, Haan, Eric, Smith, Nicholas, Sadeghpour, Azita, Davis, Erica E, Katsanis, Nicholas, Genomics, Task Force for Neonatal, Allori, Alexander, Angrist, Misha, Ashley, Patricia, Bidegain, Margarita, Boyd, Brita, Chambers, Eileen, Cope, Heidi, Cotten, C Michael, Curington, Theresa, Ellestad, Sarah, Fisher, Kimberley, French, Amanda, Gallentine, William, Goldberg, Ronald, Hill, Kevin, Kansagra, Sujay, Katsanis, Sara, Kurtzberg, Joanne, Marcus, Jeffrey, McDonald, Marie, Mikati, Mohammed, Miller, Stephen, Murtha, Amy, Perilla, Yezmin, Pizoli, Carolyn, Purves, Todd, Ross, Sherry, Smith, Edward, Wiener, John, Corbett, Mark A, MacLennan, Alastair H, Gecz, Jozef, Biskup, Saskia, Goldmann, Eva, Rodan, Lance H, Kichula, Elizabeth, Segal, Eric, Jackson, Kelly E, Asamoah, Alexander, Dimmock, David, McCarrier, Julie, Botto, Lorenzo D, Filloux, Francis, Tvrdik, Tatiana, and Cascino, Gregory D

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Neurodegenerative, Brain Disorders, Neurosciences, Epilepsy, Pediatric, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adolescent, Adult, Calcium Channels, R-Type, Cation Transport Proteins, Child, Child, Preschool, Contracture, Dyskinesias, Female, Genetic Variation, Humans, Infant, Male, Megalencephaly, Neurodevelopmental Disorders, Spasms, Infantile, Task Force for Neonatal Genomics, Deciphering Developmental Disorders Study, CACNA1E, ion channel, arthrogryposis, calcium channel, epilepsy, Biological Sciences, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

Published
2018

9. Validating and automating learning of cardiometabolic polygenic risk scores from direct-to-consumer genetic and phenotypic data: implications for scaling precision health research

Author

Lopez-Pineda, Arturo, Vernekar, Manvi, Moreno-Grau, Sonia, Rojas-Muñoz, Agustin, Moatamed, Babak, Lee, Ming Ta Michael, Nava-Aguilar, Marco A., Gonzalez-Arroyo, Gilberto, Numakura, Kensuke, Matsuda, Yuta, Ioannidis, Alexander, Katsanis, Nicholas, Takano, Tomohiro, and Bustamante, Carlos D.

Published
2022
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12. Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia

Author

Guissart, Claire, Latypova, Xenia, Rollier, Paul, Khan, Tahir N, Stamberger, Hannah, McWalter, Kirsty, Cho, Megan T, Kjaergaard, Susanne, Weckhuysen, Sarah, Lesca, Gaetan, Besnard, Thomas, Õunap, Katrin, Schema, Lynn, Chiocchetti, Andreas G, McDonald, Marie, de Bellescize, Julitta, Vincent, Marie, Van Esch, Hilde, Sattler, Shannon, Forghani, Irman, Thiffault, Isabelle, Freitag, Christine M, Barbouth, Deborah Sara, Cadieux-Dion, Maxime, Willaert, Rebecca, Sacoto, Maria J Guillen, Safina, Nicole P, Dubourg, Christèle, Grote, Lauren, Carré, Wilfrid, Saunders, Carol, Pajusalu, Sander, Farrow, Emily, Boland, Anne, Karlowicz, Danielle Hays, Deleuze, Jean-François, Wojcik, Monica H, Pressman, Rena, Isidor, Bertrand, Vogels, Annick, Van Paesschen, Wim, Al-Gazali, Lihadh, Shamsi, Aisha Mohamed Al, Claustres, Mireille, Pujol, Aurora, Sanders, Stephan J, Rivier, François, Leboucq, Nicolas, Cogné, Benjamin, Sasorith, Souphatta, Sanlaville, Damien, Retterer, Kyle, Odent, Sylvie, Katsanis, Nicholas, Bézieau, Stéphane, Koenig, Michel, Davis, Erica E, Pasquier, Laurent, and Küry, Sébastien

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Intellectual and Developmental Disabilities (IDD), Neurodegenerative, Neurosciences, Pediatric, Rare Diseases, Brain Disorders, Autism, Mental Health, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adolescent, Adult, Aged, 80 and over, Alleles, Animals, Autistic Disorder, Brain, Cerebellar Ataxia, Child, Child, Preschool, DNA Copy Number Variations, Disease Models, Animal, Female, Genes, Dominant, Genetic Complementation Test, Humans, Intellectual Disability, Larva, Magnetic Resonance Imaging, Male, Middle Aged, Mutation, Missense, Nuclear Receptor Subfamily 1, Group F, Member 1, Purkinje Cells, Syndrome, Zebrafish, RORA, autistic features, cerebellar ataxia, dual molecular effects, epilepsy, intellectual disability, neurodevelopmental disorder, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome.

Published
2018

13. Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights.

Author

Gusev, Alexander, Mancuso, Nicholas, Won, Hyejung, Kousi, Maria, Finucane, Hilary K, Reshef, Yakir, Song, Lingyun, Safi, Alexias, Schizophrenia Working Group of the Psychiatric Genomics Consortium, McCarroll, Steven, Neale, Benjamin M, Ophoff, Roel A, O'Donovan, Michael C, Crawford, Gregory E, Geschwind, Daniel H, Katsanis, Nicholas, Sullivan, Patrick F, Pasaniuc, Bogdan, and Price, Alkes L

Subjects
Schizophrenia Working Group of the Psychiatric Genomics Consortium, Brain, Chromatin, Animals, Zebrafish, Humans, Genetic Predisposition to Disease, Mitogen-Activated Protein Kinase 3, Microtubule-Associated Proteins, Zebrafish Proteins, Gene Expression Profiling, Schizophrenia, Gene Dosage, Multifactorial Inheritance, Quantitative Trait Loci, Protein Phosphatase 2, Genome-Wide Association Study, Human Genome, Genetics, Mental Health, Neurosciences, Brain Disorders, Serious Mental Illness, 2.1 Biological and endogenous factors, Mental health, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

Genome-wide association studies (GWAS) have identified over 100 risk loci for schizophrenia, but the causal mechanisms remain largely unknown. We performed a transcriptome-wide association study (TWAS) integrating a schizophrenia GWAS of 79,845 individuals from the Psychiatric Genomics Consortium with expression data from brain, blood, and adipose tissues across 3,693 primarily control individuals. We identified 157 TWAS-significant genes, of which 35 did not overlap a known GWAS locus. Of these 157 genes, 42 were associated with specific chromatin features measured in independent samples, thus highlighting potential regulatory targets for follow-up. Suppression of one identified susceptibility gene, mapk3, in zebrafish showed a significant effect on neurodevelopmental phenotypes. Expression and splicing from the brain captured most of the TWAS effect across all genes. This large-scale connection of associations to target genes, tissues, and regulatory features is an essential step in moving toward a mechanistic understanding of GWAS.

Published
2018

14. Temperature-activated ion channels in neural crest cells confer maternal fever–associated birth defects

Author

Hutson, Mary R, Keyte, Anna L, Hernández-Morales, Miriam, Gibbs, Eric, Kupchinsky, Zachary A, Argyridis, Ioannis, Erwin, Kyle N, Pegram, Kelly, Kneifel, Margaret, Rosenberg, Paul B, Matak, Pavle, Xie, Luke, Grandl, Jörg, Davis, Erica E, Katsanis, Nicholas, Liu, Chunlei, and Benner, Eric J

Subjects
Stem Cell Research, Pediatric, Neurosciences, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Animals, Chick Embryo, Chickens, Congenital Abnormalities, Female, Fever, Heart Failure, Maternal-Fetal Exchange, Mice, Mice, Inbred C57BL, Neural Crest, Pregnancy, TRPV Cation Channels, Zebrafish, Biochemistry and Cell Biology
Abstract

Birth defects of the heart and face are common, and most have no known genetic cause, suggesting a role for environmental factors. Maternal fever during the first trimester is an environmental risk factor linked to these defects. Neural crest cells are precursor populations essential to the development of both at-risk tissues. We report that two heat-activated transient receptor potential (TRP) ion channels, TRPV1 and TRPV4, were present in neural crest cells during critical windows of heart and face development. TRPV1 antagonists protected against the development of hyperthermia-induced defects in chick embryos. Treatment with chemical agonists of TRPV1 or TRPV4 replicated hyperthermia-induced birth defects in chick and zebrafish embryos. To test whether transient TRPV channel permeability in neural crest cells was sufficient to induce these defects, we engineered iron-binding modifications to TRPV1 and TRPV4 that enabled remote and noninvasive activation of these channels in specific cellular locations and at specific developmental times in chick embryos with radio-frequency electromagnetic fields. Transient stimulation of radio frequency-controlled TRP channels in neural crest cells replicated fever-associated defects in developing chick embryos. Our data provide a previously undescribed mechanism for congenital defects, whereby hyperthermia activates ion channels that negatively affect fetal development.

Published
2017

15. De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder

Author

Küry, Sébastien, Besnard, Thomas, Ebstein, Frédéric, Khan, Tahir N, Gambin, Tomasz, Douglas, Jessica, Bacino, Carlos A, Craigen, William J, Sanders, Stephan J, Lehmann, Andrea, Latypova, Xénia, Khan, Kamal, Pacault, Mathilde, Sacharow, Stephanie, Glaser, Kimberly, Bieth, Eric, Perrin-Sabourin, Laurence, Jacquemont, Marie-Line, Cho, Megan T, Roeder, Elizabeth, Denommé-Pichon, Anne-Sophie, Monaghan, Kristin G, Yuan, Bo, Xia, Fan, Simon, Sylvain, Bonneau, Dominique, Parent, Philippe, Gilbert-Dussardier, Brigitte, Odent, Sylvie, Toutain, Annick, Pasquier, Laurent, Barbouth, Deborah, Shaw, Chad A, Patel, Ankita, Smith, Janice L, Bi, Weimin, Schmitt, Sébastien, Deb, Wallid, Nizon, Mathilde, Mercier, Sandra, Vincent, Marie, Rooryck, Caroline, Malan, Valérie, Briceño, Ignacio, Gómez, Alberto, Nugent, Kimberly M, Gibson, James B, Cogné, Benjamin, Lupski, James R, Stessman, Holly AF, Eichler, Evan E, Retterer, Kyle, Yang, Yaping, Redon, Richard, Katsanis, Nicholas, Rosenfeld, Jill A, Kloetzel, Peter-Michael, Golzio, Christelle, Bézieau, Stéphane, Stankiewicz, Paweł, and Isidor, Bertrand

Subjects
Biochemistry and Cell Biology, Bioinformatics and Computational Biology, Biological Sciences, Neurosciences, Congenital Structural Anomalies, Dental/Oral and Craniofacial Disease, Biotechnology, Genetics, Intellectual and Developmental Disabilities (IDD), Human Genome, Pediatric, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Adolescent, Animals, Child, Child, Preschool, DNA Copy Number Variations, Disease Models, Animal, Down-Regulation, Female, Gene Deletion, Humans, Infant, Intellectual Disability, Male, Microcephaly, Neurodevelopmental Disorders, Polymorphism, Single Nucleotide, Proteasome Endopeptidase Complex, Zebrafish, PSMD12, RPN5, intellectual disability, proteasome 26S, syndromic neurodevelopmental disorder, ubiquitin, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.

Published
2017

16. Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy

Author

Kousi, Maria, Söylemez, Onuralp, Ozanturk, Aysegül, Mourtzi, Niki, Akle, Sebastian, Jungreis, Irwin, Muller, Jean, Cassa, Christopher A., Brand, Harrison, Mokry, Jill Anne, Wolf, Maxim Y., Sadeghpour, Azita, McFadden, Kelsey, Lewis, Richard A., Talkowski, Michael E., Dollfus, Hélène, Kellis, Manolis, Davis, Erica E., Sunyaev, Shamil R., and Katsanis, Nicholas

Published
2020
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18. Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling

Author

Blok, Lot Snijders, Madsen, Erik, Juusola, Jane, Gilissen, Christian, Baralle, Diana, Reijnders, Margot RF, Venselaar, Hanka, Helsmoortel, Céline, Cho, Megan T, Hoischen, Alexander, Vissers, Lisenka ELM, Koemans, Tom S, Wissink-Lindhout, Willemijn, Eichler, Evan E, Romano, Corrado, Van Esch, Hilde, Stumpel, Connie, Vreeburg, Maaike, Smeets, Eric, Oberndorff, Karin, van Bon, Bregje WM, Shaw, Marie, Gecz, Jozef, Haan, Eric, Bienek, Melanie, Jensen, Corinna, Loeys, Bart L, Van Dijck, Anke, Innes, A Micheil, Racher, Hilary, Vermeer, Sascha, Di Donato, Nataliya, Rump, Andreas, Tatton-Brown, Katrina, Parker, Michael J, Henderson, Alex, Lynch, Sally A, Fryer, Alan, Ross, Alison, Vasudevan, Pradeep, Kini, Usha, Newbury-Ecob, Ruth, Chandler, Kate, Male, Alison, Study, the DDD, Dijkstra, Sybe, Schieving, Jolanda, Giltay, Jacques, van Gassen, Koen LI, Schuurs-Hoeijmakers, Janneke, Tan, Perciliz L, Pediaditakis, Igor, Haas, Stefan A, Retterer, Kyle, Reed, Patrick, Monaghan, Kristin G, Haverfield, Eden, Natowicz, Marvin, Myers, Angela, Kruer, Michael C, Stein, Quinn, Strauss, Kevin A, Brigatti, Karlla W, Keating, Katherine, Burton, Barbara K, Kim, Katherine H, Charrow, Joel, Norman, Jennifer, Foster-Barber, Audrey, Kline, Antonie D, Kimball, Amy, Zackai, Elaine, Harr, Margaret, Fox, Joyce, McLaughlin, Julie, Lindstrom, Kristin, Haude, Katrina M, van Roozendaal, Kees, Brunner, Han, Chung, Wendy K, Kooy, R Frank, Pfundt, Rolph, Kalscheuer, Vera, Mehta, Sarju G, Katsanis, Nicholas, and Kleefstra, Tjitske

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Intellectual and Developmental Disabilities (IDD), Human Genome, Clinical Research, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Amino Acid Substitution, Animals, Base Sequence, DEAD-box RNA Helicases, Embryo, Nonmammalian, Exome, Female, Gene Dosage, Humans, Intellectual Disability, Male, Molecular Sequence Data, Mutation, Missense, Phenotype, Sequence Analysis, DNA, Sex Characteristics, Wnt Signaling Pathway, Zebrafish, DDD Study, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations.

Published
2015

19. The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes

Author

Waters, Aoife M, Asfahani, Rowan, Carroll, Paula, Bicknell, Louise, Lescai, Francesco, Bright, Alison, Chanudet, Estelle, Brooks, Anthony, Christou-Savina, Sonja, Osman, Guled, Walsh, Patrick, Bacchelli, Chiara, Chapgier, Ariane, Vernay, Bertrand, Bader, David M, Deshpande, Charu, O' Sullivan, Mary, Ocaka, Louise, Stanescu, Horia, Stewart, Helen S, Hildebrandt, Friedhelm, Otto, Edgar, Johnson, Colin A, Szymanska, Katarzyna, Katsanis, Nicholas, Davis, Erica, Kleta, Robert, Hubank, Mike, Doxsey, Stephen, Jackson, Andrew, Stupka, Elia, Winey, Mark, and Beales, Philip L

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Rare Diseases, Pediatric, Human Genome, Congenital Structural Anomalies, Aetiology, 2.1 Biological and endogenous factors, Animals, Centrioles, Chromosomal Proteins, Non-Histone, Cilia, Exome, Female, Fetus, Genetics, Medical, HEK293 Cells, High-Throughput Nucleotide Sequencing, Humans, Male, Mice, Microcephaly, Microfilament Proteins, Mutation, NIH 3T3 Cells, Pedigree, Pregnancy, Zebrafish, CENPF, Ciliopathy, Clinical genetics, Molecular genetics, Medical and Health Sciences, Genetics & Heredity, Clinical sciences
Abstract

BackgroundMutations in microtubule-regulating genes are associated with disorders of neuronal migration and microcephaly. Regulation of centriole length has been shown to underlie the pathogenesis of certain ciliopathy phenotypes. Using a next-generation sequencing approach, we identified mutations in a novel centriolar disease gene in a kindred with an embryonic lethal ciliopathy phenotype and in a patient with primary microcephaly.Methods and resultsWhole exome sequencing data from a non-consanguineous Caucasian kindred exhibiting mid-gestation lethality and ciliopathic malformations revealed two novel non-synonymous variants in CENPF, a microtubule-regulating gene. All four affected fetuses showed segregation for two mutated alleles [IVS5-2A>C, predicted to abolish the consensus splice-acceptor site from exon 6; c.1744G>T, p.E582X]. In a second unrelated patient exhibiting microcephaly, we identified two CENPF mutations [c.1744G>T, p.E582X; c.8692 C>T, p.R2898X] by whole exome sequencing. We found that CENP-F colocalised with Ninein at the subdistal appendages of the mother centriole in mouse inner medullary collecting duct cells. Intraflagellar transport protein-88 (IFT-88) colocalised with CENP-F along the ciliary axonemes of renal epithelial cells in age-matched control human fetuses but did not in truncated cilia of mutant CENPF kidneys. Pairwise co-immunoprecipitation assays of mitotic and serum-starved HEKT293 cells confirmed that IFT88 precipitates with endogenous CENP-F.ConclusionsOur data identify CENPF as a new centriolar disease gene implicated in severe human ciliopathy and microcephaly related phenotypes. CENP-F has a novel putative function in ciliogenesis and cortical neurogenesis.

Published
2015

20. Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

Author

Frints, Suzanna G. M., Ozanturk, Aysegul, Rodríguez Criado, Germán, Grasshoff, Ute, de Hoon, Bas, Field, Michael, Manouvrier-Hanu, Sylvie, E. Hickey, Scott, Kammoun, Molka, Gripp, Karen W., Bauer, Claudia, Schroeder, Christopher, Toutain, Annick, Mihalic Mosher, Theresa, Kelly, Benjamin J., White, Peter, Dufke, Andreas, Rentmeester, Eveline, Moon, Sungjin, Koboldt, Daniel C, van Roozendaal, Kees E. P., Hu, Hao, Haas, Stefan A., Ropers, Hans-Hilger, Murray, Lucinda, Haan, Eric, Shaw, Marie, Carroll, Renee, Friend, Kathryn, Liebelt, Jan, Hobson, Lynne, De Rademaeker, Marjan, Geraedts, Joep, Fryns, Jean-Pierre, Vermeesch, Joris, Raynaud, Martine, Riess, Olaf, Gribnau, Joost, Katsanis, Nicholas, Devriendt, Koen, Bauer, Peter, Gecz, Jozef, Golzio, Christelle, Gontan, Cristina, and Kalscheuer, Vera M.

Published
2019
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22. Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma.

Author

Carnes, Megan Ulmer, Liu, Yangfan P, Allingham, R Rand, Whigham, Benjamin T, Havens, Shane, Garrett, Melanie E, Qiao, Chunyan, NEIGHBORHOOD Consortium Investigators, Katsanis, Nicholas, Wiggs, Janey L, Pasquale, Louis R, Ashley-Koch, Allison, Oh, Edwin C, and Hauser, Michael A

Subjects
NEIGHBORHOOD Consortium Investigators, Eye, Optic Nerve, Chromosomes, Human, Pair 9, Humans, Glaucoma, Open-Angle, Homeodomain Proteins, Trans-Activators, Intraocular Pressure, Alleles, Aged, Female, Genome-Wide Association Study, Chromosomes, Human, Pair 9, Glaucoma, Open-Angle, Genetics, Developmental Biology
Abstract

Glaucoma is a leading cause of blindness worldwide. Primary open-angle glaucoma (POAG) is the most common subtype and is a complex trait with multigenic inheritance. Genome-wide association studies have previously identified a significant association between POAG and the SIX6 locus (rs10483727, odds ratio (OR) = 1.32, p = 3.87×10(-11)). SIX6 plays a role in ocular development and has been associated with the morphology of the optic nerve. We sequenced the SIX6 coding and regulatory regions in 262 POAG cases and 256 controls and identified six nonsynonymous coding variants, including five rare and one common variant, Asn141His (rs33912345), which was associated significantly with POAG (OR = 1.27, p = 4.2×10(-10)) in the NEIGHBOR/GLAUGEN datasets. These variants were tested in an in vivo Danio rerio (zebrafish) complementation assay to evaluate ocular metrics such as eye size and optic nerve structure. Five variants, found primarily in POAG cases, were hypomorphic or null, while the sixth variant, found only in controls, was benign. One variant in the SIX6 enhancer increased expression of SIX6 and disrupted its regulation. Finally, to our knowledge for the first time, we have identified a clinical feature in POAG patients that appears to be dependent upon SIX6 genotype: patients who are homozygous for the SIX6 risk allele (His141) have a statistically thinner retinal nerve fiber layer than patients homozygous for the SIX6 non-risk allele (Asn141). Our results, in combination with previous SIX6 work, lead us to hypothesize that SIX6 risk variants disrupt the development of the neural retina, leading to a reduced number of retinal ganglion cells, thereby increasing the risk of glaucoma-associated vision loss.

Published
2014

23. Discovery and Functional Annotation of SIX6 Variants in Primary Open-Angle Glaucoma

Author

Ulmer Carnes, Megan, Liu, Yangfan P, Allingham, R Rand, Whigham, Benjamin T, Havens, Shane, Garrett, Melanie E, Qiao, Chunyan, Katsanis, Nicholas, Wiggs, Janey L, Pasquale, Louis R, Ashley-Koch, Allison, Oh, Edwin C, and Hauser, Michael A

Subjects
Human Genome, Aging, Neurodegenerative, Neurosciences, Biotechnology, Genetics, Eye Disease and Disorders of Vision, 2.1 Biological and endogenous factors, Aetiology, Eye, Aged, Alleles, Chromosomes, Human, Pair 9, Female, Genome-Wide Association Study, Glaucoma, Open-Angle, Homeodomain Proteins, Humans, Intraocular Pressure, Optic Nerve, Trans-Activators, NEIGHBORHOOD Consortium Investigators, Developmental Biology
Abstract

Glaucoma is a leading cause of blindness worldwide. Primary open-angle glaucoma (POAG) is the most common subtype and is a complex trait with multigenic inheritance. Genome-wide association studies have previously identified a significant association between POAG and the SIX6 locus (rs10483727, odds ratio (OR) = 1.32, p = 3.87×10(-11)). SIX6 plays a role in ocular development and has been associated with the morphology of the optic nerve. We sequenced the SIX6 coding and regulatory regions in 262 POAG cases and 256 controls and identified six nonsynonymous coding variants, including five rare and one common variant, Asn141His (rs33912345), which was associated significantly with POAG (OR = 1.27, p = 4.2×10(-10)) in the NEIGHBOR/GLAUGEN datasets. These variants were tested in an in vivo Danio rerio (zebrafish) complementation assay to evaluate ocular metrics such as eye size and optic nerve structure. Five variants, found primarily in POAG cases, were hypomorphic or null, while the sixth variant, found only in controls, was benign. One variant in the SIX6 enhancer increased expression of SIX6 and disrupted its regulation. Finally, to our knowledge for the first time, we have identified a clinical feature in POAG patients that appears to be dependent upon SIX6 genotype: patients who are homozygous for the SIX6 risk allele (His141) have a statistically thinner retinal nerve fiber layer than patients homozygous for the SIX6 non-risk allele (Asn141). Our results, in combination with previous SIX6 work, lead us to hypothesize that SIX6 risk variants disrupt the development of the neural retina, leading to a reduced number of retinal ganglion cells, thereby increasing the risk of glaucoma-associated vision loss.

Published
2014

25. Mutations in FAM50A suggest that Armfield XLID syndrome is a spliceosomopathy

Author

Lee, Yu-Ri, Khan, Kamal, Armfield-Uhas, Kim, Srikanth, Sujata, Thompson, Nicola A., Pardo, Mercedes, Yu, Lu, Norris, Joy W., Peng, Yunhui, Gripp, Karen W., Aleck, Kirk A., Li, Chumei, Spence, Ed, Choi, Tae-Ik, Kwon, Soo Jeong, Park, Hee-Moon, Yu, Daseuli, Heo, Won Do, Mooney, Marie R., Baig, Shahid M., Wentzensen, Ingrid M., Telegrafi, Aida, McWalter, Kirsty, Moreland, Trevor, Roadhouse, Chelsea, Ramsey, Keri, Lyons, Michael J., Skinner, Cindy, Alexov, Emil, Katsanis, Nicholas, Stevenson, Roger E., Choudhary, Jyoti S., Adams, David J., Kim, Cheol-Hee, Davis, Erica E., and Schwartz, Charles E.

Published
2020
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26. CFAP45 deficiency causes situs abnormalities and asthenospermia by disrupting an axonemal adenine nucleotide homeostasis module

Author

Dougherty, Gerard W., Mizuno, Katsutoshi, Nöthe-Menchen, Tabea, Ikawa, Yayoi, Boldt, Karsten, Ta-Shma, Asaf, Aprea, Isabella, Minegishi, Katsura, Pang, Yuan-Ping, Pennekamp, Petra, Loges, Niki T., Raidt, Johanna, Hjeij, Rim, Wallmeier, Julia, Mussaffi, Huda, Perles, Zeev, Elpeleg, Orly, Rabert, Franziska, Shiratori, Hidetaka, Letteboer, Stef J., Horn, Nicola, Young, Samuel, Strünker, Timo, Stumme, Friederike, Werner, Claudius, Olbrich, Heike, Takaoka, Katsuyoshi, Ide, Takahiro, Twan, Wang Kyaw, Biebach, Luisa, Große-Onnebrink, Jörg, Klinkenbusch, Judith A., Praveen, Kavita, Bracht, Diana C., Höben, Inga M., Junger, Katrin, Gützlaff, Jana, Cindrić, Sandra, Aviram, Micha, Kaiser, Thomas, Memari, Yasin, Dzeja, Petras P., Dworniczak, Bernd, Ueffing, Marius, Roepman, Ronald, Bartscherer, Kerstin, Katsanis, Nicholas, Davis, Erica E., Amirav, Israel, Hamada, Hiroshi, and Omran, Heymut

Published
2020
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27. A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition

Author

Garcia-Gonzalo, Francesc R, Corbit, Kevin C, Sirerol-Piquer, María Salomé, Ramaswami, Gokul, Otto, Edgar A, Noriega, Thomas R, Seol, Allen D, Robinson, Jon F, Bennett, Christopher L, Josifova, Dragana J, García-Verdugo, José Manuel, Katsanis, Nicholas, Hildebrandt, Friedhelm, and Reiter, Jeremy F

Subjects
Biochemistry and Cell Biology, Biological Sciences, Rare Diseases, Pediatric, Abnormalities, Multiple, Animals, Cell Membrane, Cerebellar Diseases, Cerebellum, Chickens, Cilia, Ciliary Motility Disorders, Encephalocele, Eye Abnormalities, Humans, Kidney Diseases, Cystic, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Morphogenesis, Mutation, Organ Specificity, Peptide Fragments, Polycystic Kidney Diseases, Rabbits, Retina, Retinitis Pigmentosa, Signal Transduction, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology, Genetics
Abstract

Mutations affecting ciliary components cause ciliopathies. As described here, we investigated Tectonic1 (Tctn1), a regulator of mouse Hedgehog signaling, and found that it is essential for ciliogenesis in some, but not all, tissues. Cell types that do not require Tctn1 for ciliogenesis require it to localize select membrane-associated proteins to the cilium, including Arl13b, AC3, Smoothened and Pkd2. Tctn1 forms a complex with multiple ciliopathy proteins associated with Meckel and Joubert syndromes, including Mks1, Tmem216, Tmem67, Cep290, B9d1, Tctn2 and Cc2d2a. Components of this complex co-localize at the transition zone, a region between the basal body and ciliary axoneme. Like Tctn1, loss of Tctn2, Tmem67 or Cc2d2a causes tissue-specific defects in ciliogenesis and ciliary membrane composition. Consistent with a shared function for complex components, we identified a mutation in TCTN1 that causes Joubert syndrome. Thus, a transition zone complex of Meckel and Joubert syndrome proteins regulates ciliary assembly and trafficking, suggesting that transition zone dysfunction is the cause of these ciliopathies.

Published
2011

31. Global Biobank Meta-analysis Initiative: Powering genetic discovery across human disease

Author

Zhou, Wei, Kanai, Masahiro, Wu, Kuan-Han H, Rasheed, Humaira, Tsuo, Kristin, Hirbo, Jibril B, Wang, Ying, Bhattacharya, Arjun, Zhao, Huiling, Namba, Shinichi, Surakka, Ida, Wolford, Brooke N, Lo Faro, Valeria, Lopera-Maya, Esteban A, Läll, Kristi, Favé, Marie-Julie, Partanen, Juulia J, Chapman, Sinéad B, Karjalainen, Juha, Kurki, Mitja, Maasha, Mutaamba, Brumpton, Ben M, Chavan, Sameer, Chen, Tzu-Ting, Daya, Michelle, Ding, Yi, Feng, Yen-Chen A, Guare, Lindsay A, Gignoux, Christopher R, Graham, Sarah E, Hornsby, Whitney E, Ingold, Nathan, Ismail, Said I, Johnson, Ruth, Laisk, Triin, Lin, Kuang, Lv, Jun, Millwood, Iona Y, Moreno-Grau, Sonia, Nam, Kisung, Palta, Priit, Pandit, Anita, Preuss, Michael H, Saad, Chadi, Setia-Verma, Shefali, Thorsteinsdottir, Unnur, Uzunovic, Jasmina, Verma, Anurag, Zawistowski, Matthew, Zhong, Xue, Afifi, Nahla, Al-Dabhani, Kawthar M, Al Thani, Asma, Bradford, Yuki, Campbell, Archie, Crooks, Kristy, De Bock, Geertruida H, Damrauer, Scott M, Douville, Nicholas J, Finer, Sarah, Fritsche, Lars G, Fthenou, Eleni, Gonzalez-Arroyo, Gilberto, Griffiths, Christopher J, Guo, Yu, Hunt, Karen A, Ioannidis, Alexander, Jansonius, Nomdo M, Konuma, Takahiro, Lee, Ming Ta Michael, Lopez-Pineda, Arturo, Matsuda, Yuta, Marioni, Riccardo E, Moatamed, Babak, Nava-Aguilar, Marco A, Numakura, Kensuke, Patil, Snehal, Rafaels, Nicholas, Richmond, Anne, Rojas-Muñoz, Agustin, Shortt, Jonathan A, Straub, Peter, Tao, Ran, Vanderwerff, Brett, Vernekar, Manvi, Veturi, Yogasudha, Barnes, Kathleen C, Boezen, Marike, Chen, Zhengming, Chen, Chia-Yen, Cho, Judy, Smith, George Davey, Finucane, Hilary K, Franke, Lude, Gamazon, Eric R, Ganna, Andrea, Gaunt, Tom R, Ge, Tian, Huang, Hailiang, Huffman, Jennifer, Katsanis, Nicholas, Koskela, Jukka T, Lajonchere, Clara, Law, Matthew H, Li, Liming, Lindgren, Cecilia M, Loos, Ruth JF, MacGregor, Stuart, Matsuda, Koichi, Olsen, Catherine M, Porteous, David J, Shavit, Jordan A, Snieder, Harold, Takano, Tomohiro, Trembath, Richard C, Vonk, Judith M, Whiteman, David C, Wicks, Stephen J, Wijmenga, Cisca, Wright, John, Zheng, Jie, Zhou, Xiang, Awadalla, Philip, Boehnke, Michael, Bustamante, Carlos D, Cox, Nancy J, Fatumo, Segun, Geschwind, Daniel H, Hayward, Caroline, Hveem, Kristian, Kenny, Eimear E, Lee, Seunggeun, Lin, Yen-Feng, Mbarek, Hamdi, Mägi, Reedik, Martin, Hilary C, Medland, Sarah E, Okada, Yukinori, Palotie, Aarno V, Pasaniuc, Bogdan, Rader, Daniel J, Ritchie, Marylyn D, Sanna, Serena, Smoller, Jordan W, Stefansson, Kari, Van Heel, David A, Walters, Robin G, Zöllner, Sebastian, Biobank Of The Americas, Biobank Japan Project, BioMe, BioVU, CanPath-Ontario Health Study, China Kadoorie Biobank Collaborative Group, Colorado Center For Personalized Medicine, DeCODE Genetics, Estonian Biobank, FinnGen, Generation Scotland, Genes & Health Research Team, LifeLines, Mass General Brigham Biobank, Michigan Genomics Initiative, National Biobank Of Korea, Penn Medicine BioBank, Qatar Biobank, QSkin Sun And Health Study, Taiwan Biobank, HUNT Study, UCLA ATLAS Community Health Initiative, Uganda Genome Resource, UK Biobank, Martin, Alicia R, Willer, Cristen J, Daly, Mark J, Neale, Benjamin M, Namba, Shinichi [0000-0002-7486-3146], Guare, Lindsay A [0000-0001-6988-5319], Palta, Priit [0000-0001-9320-7008], de Bock, Geertruida H [0000-0003-3104-4471], Finer, Sarah [0000-0002-2684-4653], Jansonius, Nomdo M [0000-0002-6495-6568], Rojas-Muñoz, Agustin [0000-0001-7594-0599], Gamazon, Eric R [0000-0003-4204-8734], Ganna, Andrea [0000-0002-8147-240X], Koskela, Jukka T [0000-0002-0154-7222], MacGregor, Stuart [0000-0001-6731-8142], Palotie, Aarno V [0000-0002-2527-5874], and Apollo - University of Cambridge Repository

Subjects
biobank, meta-analysis, genetic association studies, GWAS, ancestry diversity, phenotype harmonization
Abstract

Funder: Biogen, Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)-a collaborative network of 23 biobanks from 4 continents representing more than 2.2 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWASs generated using harmonized genotypes and phenotypes from member biobanks for 14 exemplar diseases and endpoints. This strategy validates that GWASs conducted in diverse biobanks can be integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics. This collaborative effort improves GWAS power for diseases, benefits understudied diseases, and improves risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of human diseases and traits.

Published
2023
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35. Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency

Author

Balasubramanian, Ravikumar, Choi, Jin-Ho, Francescatto, Ludmila, Willer, Jason, Horton, Edward R., Asimacopoulos, Eleni P., Stankovic, Konstantina M., Plummer, Lacey, Buck, Cassandra L., Quinton, Richard, Nebesio, Todd D., Mericq, Veronica, Merino, Paulina M., Meyer, Brian F., Monies, Dorota, Gusella, James F., Tassan, Nada Al, Katsanis, Nicholas, and Crowley, William F.

Published
2014

38. A cross-disorder dosage sensitivity map of the human genome

Author

Collins, Ryan L., primary, Glessner, Joseph T., additional, Porcu, Eleonora, additional, Lepamets, Maarja, additional, Brandon, Rhonda, additional, Lauricella, Christopher, additional, Han, Lide, additional, Morley, Theodore, additional, Niestroj, Lisa-Marie, additional, Ulirsch, Jacob, additional, Everett, Selin, additional, Howrigan, Daniel P., additional, Boone, Philip M., additional, Fu, Jack, additional, Karczewski, Konrad J., additional, Kellaris, Georgios, additional, Lowther, Chelsea, additional, Lucente, Diane, additional, Mohajeri, Kiana, additional, Nõukas, Margit, additional, Nuttle, Xander, additional, Samocha, Kaitlin E., additional, Trinh, Mi, additional, Ullah, Farid, additional, Võsa, Urmo, additional, Hurles, Matthew E., additional, Aradhya, Swaroop, additional, Davis, Erica E., additional, Finucane, Hilary, additional, Gusella, James F., additional, Janze, Aura, additional, Katsanis, Nicholas, additional, Matyakhina, Ludmila, additional, Neale, Benjamin M., additional, Sanders, David, additional, Warren, Stephanie, additional, Hodge, Jennelle C., additional, Lal, Dennis, additional, Ruderfer, Douglas M., additional, Meck, Jeanne, additional, Mägi, Reedik, additional, Esko, Tõnu, additional, Reymond, Alexandre, additional, Kutalik, Zoltán, additional, Hakonarson, Hakon, additional, Sunyaev, Shamil, additional, Brand, Harrison, additional, Talkowski, Michael E., additional, Metspalu, Andres, additional, Nelis, Mari, additional, and Milani, Lili, additional

Published
2022
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39. Oligogenic Disease

Author

Robinson, Jon F., Katsanis, Nicholas, Speicher, Michael R., editor, Motulsky, Arno G., editor, and Antonarakis, Stylianos E., editor

Published
2010
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40. Supplement to: Genetic drivers of kidney defects in the DiGeorge syndrome.

Author

Lopez-Rivera, Esther, Liu, Yangfan P., Verbitsky, Miguel, Anderson, Blair R., Capone, Valentina P., Otto, Edgar A., Yan, Zhonghai, Mitrotti, Adele, Martino, Jeremiah, Steers, Nicholas J., Fasel, David A., Vukojevic, Katarina, Deng, Rong, Racedo, Silvia E., Liu, Qingxue, Werth, Max, Westland, Rik, Vivante, Asaf, Makar, Gabriel S., Bodria, Monica, Sampson, Matthew G., Gillies, Christopher E., Vega-Warner, Virginia, Maiorana, Mariarosa, Petrey, Donald S., Honig, Barry, Lozanovski, Vladimir J., Salomon, Rémi, Heidet, Laurence, Carpentier, Wassila, Gaillard, Dominique, Carrea, Alba, Gesualdo, Loreto, Cusi, Daniele, Izzi, Claudia, Scolari, Francesco, van Wijk, Joanna A.E., Arapovic, Adela, Saraga-Babic, Mirna, Saraga, Marijan, Kunac, Nenad, Samii, Ali, McDonald-McGinn, Donna M., Crowley, Terrence B., Zackai, Elaine H., Drosdz, Dorota, Miklaszewska, Monika, Tkaczyk, Marcin, Sikora, Przemyslaw, Szczepanska, Maria, Mizerska-Wasiak, Malgorzata, Krzemien, Grazyna, Szmigielska, Agnieszka, Zaniew, Marcin, Darlow, John M., Puri, Prem, Barton, David, Casolari, Emilio, Furth, Susan L., Warady, Bradley A., Gucev, Zoran, Hakonarson, Hakon, Flogelova, Hana, Tasic, Velibor, Bielenska, Anna Latos, Materna-Kiryluk, Anna, Allegri, Landino, Wong, Craig S., Drummond, Iain A., DʼAgati, Vivette, Imamoto, Akira, Barasch, Jonathan M., Hildebrandt, Friedhelm, Kiryluk, Krzysztof, Lifton, Richard P., Morrow, Bernice E., Jeanpierre, Cecile, Papaioannou, Virginia E., Ghiggeri, Gian Marco, Gharavi, Ali G., Katsanis, Nicholas, and Sanna-Cherchi, Simone

Published
2017

41. Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration

Author

Muto, Valentina, Flex, Elisabetta, Kupchinsky, Zachary, Primiano, Guido, Galehdari, Hamid, Dehghani, Mohammadreza, Cecchetti, Serena, Carpentieri, Giovanna, Rizza, Teresa, Mazaheri, Neda, Sedaghat, Alireza, Vahidi Mehrjardi, Mohammad Yahya, Traversa, Alice, Di Nottia, Michela, Kousi, Maria M., Jamshidi, Yalda, Ciolfi, Andrea, Caputo, Viviana, Malamiri, Reza Azizi, Pantaleoni, Francesca, Martinelli, Simone, Jeffries, Aaron R., Zeighami, Jawaher, Sherafat, Amir, Di Giuda, Daniela, Shariati, Gholam Reza, Carrozzo, Rosalba, Katsanis, Nicholas, Maroofian, Reza, Servidei, Serenella, and Tartaglia, Marco

Published
2018
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43. List of Contributors

Author

Aigner, Bernhard, primary, Allison, W. Ted, additional, Andreatini, Roberto, additional, Antonelli, Marta, additional, Arndt, Saskia S., additional, Austin, Amazon, additional, Brand, Cristin, additional, Bukowska, Joanna, additional, Caprariello, Andrew C., additional, Carlisle, Rachel E., additional, Chaible, Lucas M., additional, Chen, Li, additional, Chen, Mengqi, additional, Chi, Thomas, additional, Choudhury, Mohammed E., additional, Clarke, Iain J., additional, Coleman, Kristine, additional, Colpo, Gabriela D., additional, Damm, Oliver S., additional, Davis, Catherine M., additional, Davis, Erica E., additional, de Lecea, Luis, additional, de Miranda, Aline S., additional, de Souza, Diogo B., additional, Dickhout, Jeffrey G., additional, Donaldson, Paul J., additional, Donnan, Geoffrey A., additional, Emoto, Yuko, additional, Feifel, David, additional, Finzi Corat, Marcus A., additional, Frasch, Martin G., additional, Fukumura, Ryutaro, additional, Fukusato, Toshio, additional, Fuller-Jackson, John-Paul, additional, Fyffe-Maricich, Sharyl, additional, Gawronska-Kozak, Barbara, additional, Getz, Godfrey S., additional, Gondo, Yoichi, additional, Henry, Belinda A., additional, Howells, David W., additional, Jamwal, Sumit, additional, Kasahara, Jiro, additional, Katsanis, Nicholas, additional, Kemp, Matthew W., additional, Kessler, Barbara, additional, Khan, Imran, additional, King, Aileen, additional, Kinoshita, Denise, additional, Klymiuk, Nikolai, additional, Koyama, Ryuta, additional, Kretzschmar, Doris, additional, Kumar, Puneet, additional, Kuncova, Jitka, additional, Kuro, Maki, additional, Kurome, Mayuko, additional, Lardelli, Michael, additional, Lawson, Heather A., additional, Lewejohann, Lars, additional, Lim, Julie C., additional, Lyons, David M., additional, Macleod, Malcolm R., additional, Makino, Shigeru, additional, Martinez-Lage, Marta, additional, Martis, Renita M., additional, Meijer, Ellen, additional, Metz, Gerlinde A.S., additional, Miller, Robert H., additional, Miura, Yuichiro, additional, Mohammed-Ali, Zahraa, additional, Musk, Gabrielle C., additional, Nademi, Samera, additional, Nalca, Aysegul, additional, Newman, Morgan, additional, Nie, Yu, additional, Nishikawa, Noriko, additional, Nomoto, Masahiro, additional, Nordquist, Rebecca E., additional, O’Collins, Victoria E., additional, Ogawa, Masatoshi, additional, Pereira-Sampaio, Marco A., additional, Praud, Jean-Paul, additional, Quevedo, João, additional, Reardon, Catherine A., additional, Regan, Christopher P., additional, Renner, Simone, additional, Ribeiro, Fabiola M., additional, Rocha, Natalia P., additional, Rodriguez-Perales, Sandra, additional, Ruiz, Sara I., additional, Saito, Masatoshi, additional, J.B. Sampaio, Francisco, additional, Schapiro, Steven J., additional, Schatzberg, Alan F., additional, Schulkin, Jay, additional, Shamchuk, Angela L., additional, Shannon, Richard P., additional, Shen, You-Tang, additional, Shilling, Paul D., additional, Stengl, Milan, additional, Stoller, Marshall L., additional, Stürzenbaum, Stephen R., additional, Sviglerova, Jitka, additional, Taguchi, Kazumi, additional, Takahashi, Yoshihisa, additional, Tanabe, Akie, additional, Tanaka, Junya, additional, Tannenbaum, Jerrold, additional, Teixeira, Antônio L., additional, Testani, Jeffrey M., additional, Tierney, Keith B., additional, Torres-Ruiz, Raul, additional, Tsubura, Airo, additional, Tsuji, Ryosuke, additional, Tzou, David T., additional, Usuda, Haruo, additional, Valvassori, Samira S., additional, van der Staay, Franz J., additional, Varela, Roger B., additional, Verdile, Giuseppe, additional, Vorontsova, Irene, additional, Wayhart, Jessica P., additional, Weed, James L., additional, Welsh, JoEllen, additional, Werler, Steffi, additional, Wistuba, Joachim, additional, Wolf, Eckhard, additional, Wünsch, Annegret, additional, Yamamoto, Toshiyuki, additional, Yokoyama, Hironori, additional, Yoshizawa, Katsuhiko, additional, Zaidan Dagli, Maria L., additional, Zhang, Jennifer Y., additional, Zhou, Yu, additional, and Zumbrun, Elizabeth E., additional

Published
2017
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45. Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene

Author

Nishiguchi, Koji M., Tearle, Richard G., Liu, Yangfan P., Oh, Edwin C., Miyake, Noriko, Benaglio, Paola, Harper, Shyana, Koskiniemi-Kuendig, Hanna, Venturini, Giulia, Sharon, Dror, Koenekoop, Robert K., Nakamura, Makoto, Kondo, Mineo, Ueno, Shinji, Yasuma, Tetsuhiro R., Beckmann, Jacques S., Ikegawa, Shiro, Matsumoto, Naomichi, Terasaki, Hiroko, Berson, Eliot L., Katsanis, Nicholas, and Rivolta, Carlo

Published
2013

49. Additional file 2 of Validating and automating learning of cardiometabolic polygenic risk scores from direct-to-consumer genetic and phenotypic data: implications for scaling precision health research

Author

Lopez-Pineda, Arturo, Vernekar, Manvi, Moreno-Grau, Sonia, Rojas-Muñoz, Agustin, Moatamed, Babak, Lee, Ming Ta Michael, Nava-Aguilar, Marco A., Gonzalez-Arroyo, Gilberto, Numakura, Kensuke, Matsuda, Yuta, Ioannidis, Alexander, Katsanis, Nicholas, Takano, Tomohiro, and Bustamante, Carlos D.

Abstract

Additional file 2. Number of variants and Genotyping Call Rate.

Published
2022
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50. Additional file 4 of Validating and automating learning of cardiometabolic polygenic risk scores from direct-to-consumer genetic and phenotypic data: implications for scaling precision health research

Author

Lopez-Pineda, Arturo, Vernekar, Manvi, Moreno-Grau, Sonia, Rojas-Muñoz, Agustin, Moatamed, Babak, Lee, Ming Ta Michael, Nava-Aguilar, Marco A., Gonzalez-Arroyo, Gilberto, Numakura, Kensuke, Matsuda, Yuta, Ioannidis, Alexander, Katsanis, Nicholas, Takano, Tomohiro, and Bustamante, Carlos D.

Abstract

Additional file 4. Predictive performance results by model.

Published
2022
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