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11. Author Correction: Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Author

Waage, J, Standl, M, Curtin, JA, Jessen, LE, Thorsen, J, Tian, C, Schoettler, N, 23andMe Research Team, AAGC collaborators, Flores, C, Abdellaoui, A, Ahluwalia, TS, Alves, AC, Amaral, AFS, Antó, JM, Arnold, A, Barreto-Luis, A, Baurecht, H, van Beijsterveldt, CEM, Bleecker, ER, Bonàs-Guarch, S, Boomsma, DI, Brix, S, Bunyavanich, S, Burchard, EG, Chen, Z, Curjuric, I, Custovic, A, den Dekker, HT, Dharmage, SC, Dmitrieva, J, Duijts, L, Ege, MJ, Gauderman, WJ, Georges, M, Gieger, C, Gilliland, F, Granell, R, Gui, H, Hansen, T, Heinrich, J, Henderson, J, Hernandez-Pacheco, N, Holt, P, Imboden, M, Jaddoe, VWV, Jarvelin, M-R, Jarvis, DL, Jensen, KK, Jónsdóttir, I, Kabesch, M, Kaprio, J, Kumar, A, Lee, Y-A, Levin, AM, Li, X, Lorenzo-Diaz, F, Melén, E, Mercader, JM, Meyers, DA, Myers, R, Nicolae, DL, Nohr, EA, Palviainen, T, Paternoster, L, Pennell, CE, Pershagen, G, Pino-Yanes, M, Probst-Hensch, NM, Rüschendorf, F, Simpson, A, Stefansson, K, Sunyer, J, Sveinbjornsson, G, Thiering, E, Thompson, PJ, Torrent, M, Torrents, D, Tung, JY, Wang, CA, Weidinger, S, Weiss, S, Willemsen, G, Williams, LK, Ober, C, Hinds, DA, Ferreira, MA, Bisgaard, H, Strachan, DP, and Bønnelykke, K

Subjects
ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION, ComputingMethodologies_COMPUTERGRAPHICS
Abstract

In the version of this article initially published, in Fig. 3, the y-axis numbering did not match the log scale indicated in the axis label. The error has been corrected in the HTML and PDF version of the article.

Published
2018

12. Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Author

Waage, J, Standl, M, Curtin, JA, Jessen, L, Thorsen, J, Tian, C, Schoettler, N, The 23andMe Research Team, AAGC Collaborators, Flores, C, Abdellaoui, A, Ahluwalia, TS, Alves, A, Amaral, AFS, Antó, JM, Arnold, A, Barreto-Luis, A, Baurecht, H, van Beijsterveldt, CEM, Bleecker, ER, Bonàs-Guarch, S, Boomsma, D, Brix, S, Bunyavanich, S, Burchard, E, Chen, Z, Curjuric, I, Custovic, A, den Dekker, HT, Dharmage, SC, Dmitrieva, J, Duijts, L, Ege, MJ, Gauderman, WJ, Georges, M, Gieger, C, Gilliland, F, Granell, R, Gui, H, Hansen, T, Heinrich, J, Henderson, J, Hernandez-Pacheco, N, Holt, P, Imboden, M, Jaddoe, VWV, Jarvelin, M-R, Jarvis, DL, Jensen, KK, Jónsdóttir, I, Kabesch, M, Kaprio, J, Kumar, A, Lee, Y-A, Levin, AM, Li, X, Lorenzo-Diaz, F, Melén, E, Mercader, JM, Meyers, DA, Myers, R, Nicolae, DL, Nohr, EA, Palviainen, T, Paternoster, L, Pennell, C, Pershagen, G, Pino-Yanes, M, Probst-Hensch, NM, Rüschendorf, F, Simpson, A, Stefansson, K, Sunyer, J, Sveinbjornsson, G, Thiering, E, Thompson, PJ, Torrent, M, Torrents, D, Tung, JY, Wang, CA, Weidinger, S, Weiss, S, Willemsen, G, Williams, LK, Ober, C, Hinds, DA, Ferreira, MA, Bisgaard, H, Strachan, DP, and Bønnelykke, K

Abstract

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis.

Published
2018

13. Erratum to: Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Author

Waage, J. (Johannes), Standl, M. (Marie), Curtin, J.A. (John), Jessen, L.E. (Leon E.), Thorsen, J. (Jonathan), Tian, C. (Chao), Schoettler, N. (Nathan), Flores, C. (Carlos), Abdellaoui, A. (Abdel), Ahluwalia, T.S. (Tarunveer Singh), Alves, A.C. (Alexessander Couto), Amaral, A.F.S. (André), Anto, J.M. (Josep), Barreto-Luis, A. (Amalia), Baurecht, H. (Hansjörg), Beijsterveldt, C.E.M. (Toos) van, Bleecker, E.R. (E.), Bonàs-Guarch, S. (Silvia), Boomsma, D.I. (Dorret), Brix, S. (Susanne), Bunyavanich, S. (Supinda), Burchard, E.G. (Esteban), Chen, Z. (Zhanghua), Curjuric, I. (Ivan), Custovic, A. (Adnan), Dekker, H.T. (Herman) den, Dharmage, S.C. (Shyamali C.), Dmitrieva, J. (Julia), Duijts, L. (Liesbeth), Ege, M. (Markus), Gauderman, W.J. (W James), Georges, M. (Michel), Gieger, C. (Christian), Gilliland, D.G. (Gary), Granell, R. (Raquel), Gui, H. (Hongsheng), Hansen, T. (Torben), Heinrich, J. (Joachim), Henderson, J. (John), Hernandez-Pacheco, N. (Natalia), Holt, P.G. (Patrick), Imboden, M. (Medea), Jaddoe, V.W.V. (Vincent), Jarvelin, M.-R. (Marjo-Riitta), Jarvis, D.L. (Deborah), Jensen, K.K. (Kamilla K.), Jonsdottir, I. (Ingileif), Kabesch, M. (Michael), Kaprio, J. (Jaakko), Kumar, A. (Ashish), Lee, Y.-A. (Young-Ae), Levin, A.M. (Albert M.), Li, X. (Xingnan), Lorenzo-Diaz, F. (Fabian), Melén, E. (Erik), Mercader, J.M. (Josep M.), Meyers, D.A. (Deborah A.), Myers, R.A. (Rachel A.), Nicolae, D. (Dan), Nohr, C. (Christian), Palviainen, T. (Teemu), Paternoster, L. (Lavinia), Pennell, C.E. (Craig E.), Pershagen, G. (Göran), Pino-Yanes, M. (Maria), Probst-Hensch, N.M. (Nicole M.), Rüschendorf, F. (Franz), Simpson, A. (Angela), Zwart, J-A. (John-Anker), Sunyer, J. (Jordi), Sveinbjornsson, G. (Gardar), Thiering, E. (Elisabeth), Thompson, P.J. (Philip J.), Torrent, M. (Maties), Torrents, D. (David), Tung, J.Y. (Joyce Y.), Wang, C.A. (Carol A.), Weidinger, S. (Stephan), Weiss, S.T. (Scott T.), Willemsen, G.A.H.M. (Gonneke), Williams, L.K. (L. Keoki), Ober, C. (Carole), Hinds, D.A. (David A.), Ferreira, M.A. (Manuel), Bisgaard, H. (Hans), Arnold, A.M. (Alice), Strachan, D.P. (David), Bønnelykke, K. (Klaus), Waage, J. (Johannes), Standl, M. (Marie), Curtin, J.A. (John), Jessen, L.E. (Leon E.), Thorsen, J. (Jonathan), Tian, C. (Chao), Schoettler, N. (Nathan), Flores, C. (Carlos), Abdellaoui, A. (Abdel), Ahluwalia, T.S. (Tarunveer Singh), Alves, A.C. (Alexessander Couto), Amaral, A.F.S. (André), Anto, J.M. (Josep), Barreto-Luis, A. (Amalia), Baurecht, H. (Hansjörg), Beijsterveldt, C.E.M. (Toos) van, Bleecker, E.R. (E.), Bonàs-Guarch, S. (Silvia), Boomsma, D.I. (Dorret), Brix, S. (Susanne), Bunyavanich, S. (Supinda), Burchard, E.G. (Esteban), Chen, Z. (Zhanghua), Curjuric, I. (Ivan), Custovic, A. (Adnan), Dekker, H.T. (Herman) den, Dharmage, S.C. (Shyamali C.), Dmitrieva, J. (Julia), Duijts, L. (Liesbeth), Ege, M. (Markus), Gauderman, W.J. (W James), Georges, M. (Michel), Gieger, C. (Christian), Gilliland, D.G. (Gary), Granell, R. (Raquel), Gui, H. (Hongsheng), Hansen, T. (Torben), Heinrich, J. (Joachim), Henderson, J. (John), Hernandez-Pacheco, N. (Natalia), Holt, P.G. (Patrick), Imboden, M. (Medea), Jaddoe, V.W.V. (Vincent), Jarvelin, M.-R. (Marjo-Riitta), Jarvis, D.L. (Deborah), Jensen, K.K. (Kamilla K.), Jonsdottir, I. (Ingileif), Kabesch, M. (Michael), Kaprio, J. (Jaakko), Kumar, A. (Ashish), Lee, Y.-A. (Young-Ae), Levin, A.M. (Albert M.), Li, X. (Xingnan), Lorenzo-Diaz, F. (Fabian), Melén, E. (Erik), Mercader, J.M. (Josep M.), Meyers, D.A. (Deborah A.), Myers, R.A. (Rachel A.), Nicolae, D. (Dan), Nohr, C. (Christian), Palviainen, T. (Teemu), Paternoster, L. (Lavinia), Pennell, C.E. (Craig E.), Pershagen, G. (Göran), Pino-Yanes, M. (Maria), Probst-Hensch, N.M. (Nicole M.), Rüschendorf, F. (Franz), Simpson, A. (Angela), Zwart, J-A. (John-Anker), Sunyer, J. (Jordi), Sveinbjornsson, G. (Gardar), Thiering, E. (Elisabeth), Thompson, P.J. (Philip J.), Torrent, M. (Maties), Torrents, D. (David), Tung, J.Y. (Joyce Y.), Wang, C.A. (Carol A.), Weidinger, S. (Stephan), Weiss, S.T. (Scott T.), Willemsen, G.A.H.M. (Gonneke), Williams, L.K. (L. Keoki), Ober, C. (Carole), Hinds, D.A. (David A.), Ferreira, M.A. (Manuel), Bisgaard, H. (Hans), Arnold, A.M. (Alice), Strachan, D.P. (David), and Bønnelykke, K. (Klaus)

Abstract

In the version of this article initially published, in Fig. 3, the _y_-axis numbering did not match the log scale indicated in the axis label. The error has been corrected in the HTML and PDF version of the article.

Published
2018
Full Text
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14. Genome-wide association study identifies the SERPINB gene cluster as a susceptibility locus for food allergy

Author

Marenholz, I., Grosche, S., Kalb, B., Rüschendorf, F., Blümchen, K., Schlags, R., Harandi, N., Price, M., Hansen, G., Seidenberg, J., Röblitz, H., Yürek, S., Tschirner, S., Hong, X., Wang, X., Homuth, G., Schmidt, C.O., Nöthen, M.M., Hübner, N., Niggemann, B., Beyer, K., and Lee, Y.A.

Subjects
Cardiovascular and Metabolic Diseases
Abstract

Genetic factors and mechanisms underlying food allergy are largely unknown. Due to heterogeneity of symptoms a reliable diagnosis is often difficult to make. Here, we report a genome-wide association study on food allergy diagnosed by oral food challenge in 497 cases and 2387 controls. We identify five loci at genome-wide significance, the clade B serpin (SERPINB) gene cluster at 18q21.3, the cytokine gene cluster at 5q31.1, the filaggrin gene, the C11orf30/LRRC32 locus, and the human leukocyte antigen (HLA) region. Stratifying the results for the causative food demonstrates that association of the HLA locus is peanut allergy-specific whereas the other four loci increase the risk for any food allergy. Variants in the SERPINB gene cluster are associated with SERPINB10 expression in leukocytes. Moreover, SERPINB genes are highly expressed in the esophagus. All identified loci are involved in immunological regulation or epithelial barrier function, emphasizing the role of both mechanisms in food allergy.

Published
2017

16. Exon-disrupting deletions ofNRXN1in idiopathic generalized epilepsy

Author

Møller, R.S., Weber, Y.G., Klitten, L.L., Trucks, H., Muhle, H., Kunz, W.S., Mefford, H.C., Franke, A., Kautza, M., Wolf, P., Dennig, D., Schreiber, S., Rückert, I.M., Wichmann, H.E., Ernst, J.P., Schurmann, C., Grabe, H.J., Tommerup, N., Stephani, U., Lerche, H., Hjalgrim, H., Helbig, I., Sander, T., Zimprich, F., Mörzinger, M., Feucht, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Jordanova, A., Kjelgaard, D.B., Lehesjoki, A.E., Siren, A., Baulac, S., Leguern, E., Von Spiczak, S., Ostertag, P., Leber, M., Leu, C., Toliat, M.R., Nürnberg, P., Hempelmann, A., Rüschendorf, F., Elger, C.E., Kleefuß Lie, A.A., Surges, R., Gaus, V., Janz, D., Schmitz, B., Klein, K.M., Reif, P.S., Oertel, W.H., Hamer, H.M., Rosenow, F., Becker, F., Marini, C., Guerrini, R., Mei, D., Norci, V., Zara, F., Striano, P., Robbiano, A., Pezzella, M., Bianchi, A., Gambardella, A., Tinuper, P., La Neve, A., Capovilla, G., Vigliano, P., Crichiutti, G., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Giallonardo, M.T., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., Koeleman, B.P.C., De Kovel, C., Lindhout, D., De Haan, G.J., Ozbeck, U., Bebek, N., Baykan, B., Ozdemir, O., Ugur, S., Kocasoy Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Yapici, Z., Ozkara, C., Caglayan, H., Yalcin, O., Yalcin, D., Turkdogan, D., Dizdarer, G., Agan, K., R. S. Møller, Y. G. Weber, L. L. Klitten, H. Truck, H. Muhle, W. S. Kunz, H. C. Mefford, A. Franke, M. Kautza, P. Wolf, D. Dennig, S. Schreiber, I. Rückert, H. Wichmann, J. P. Ernst, C. Schurmann, H. J. Grabe, N. Tommerup, U. Stephani, H. Lerche, H. Hjalgrim, I. Helbig, T. Sander, P. Tinuper, F. Bisulli, EPICURE Consortium, Suls, Arvid, Weckhuysen, Sarah, Claes, Godelieve, Deprez, Liesbet, Smets, Katrien, Van Dyck, Tine, Deconinck, Tine, De Jonghe, Peter, Jordanova, Albena, Møller, R, Weber, Yg, Klitten, Ll, Trucks, H, Muhle, H, Kunz, W, Mefford, Hc, Franke, A, Kautza, M, Wolf, P, Dennig, D, Schreiber, S, Rückert, Im, Wichmann, He, Ernst, Jp, Schurmann, C, Grabe, Hj, Tommerup, N, Stephani, U, Lerche, H, Hjalgrim, H, Helbig, I, Sander, T, Epicure, Consortium, DEL GIUDICE, Ennio, Coppola, Antonietta, and YÜCESAN, EMRAH

Subjects
Male, Idiopathic generalized epilepsy, Neuronal, Idiopathic Generalized Epilepsy, 1q21, 1 Microdeletion, Two-hit Hypothesis, Nrxn1, Neuropsychological Tests, Immunoglobulin E, Cell Adhesion Molecules, Neuronal/genetics, Adult, Age of Onset, Anticonvulsant, Exon, 1q21.1 microdeletion, Exons/genetics, Odds Ratio, Nerve Tissue Proteins/genetics, Copy-number variation, Valproic Acid/therapeutic use, Age of Onset, Neural Cell Adhesion Molecules, genetics, DNA Copy Number Variations, Electroencephalography, Epilepsy, Genetics, biology, Triazines, Anticonvulsants/therapeutic use, Electroencephalography, genetics, Family, Female, Fructose, Exons, Middle Aged, Settore MED/39 - Neuropsichiatria Infantile, Pedigree, therapeutic use, Valproic Acid, Neurology, Settore MED/26 - Neurologia, Anticonvulsants, Epilepsy, Generalized, Female, Adult, Case-Control Studies, Cell Adhesion Molecules, Neuronal, DNA Copy Number Variations, Family, Fructose, Gene Deletion, Genotype, Humans, Infant, Microarray Analysis, Nerve Tissue Proteins, Valproic Acid, analogs /&/ derivatives/therapeutic use, Gene Deletion, Genotype, Humans, Infant, Male, Microarray Analysis, Middle Aged, Nerve Tissue Protein, therapeutic use, Case-Control Studies, Cell Adhesion Molecule, drug therapy/genetics/psychology, Exon, genetics, Neuropsychological Tests, Odds Ratio, Pedigree, Triazine, Lamotrigine, NRXN1, Topiramate, Epilepsy, Generalized/drug therapy, medicine, Allele, Biology, Gene, Generalized, Point mutation, Calcium-Binding Proteins, Odds ratio, medicine.disease, Triazines/therapeutic use, Settore MED/03 - Genetica Medica, therapeutic use, biology.protein, Fructose/analogs & derivatives, Human medicine, Neurology (clinical), Two-hit hypothesis
Abstract

Summary Purpose Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs). Methods We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays. Key Findings We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p = 0.0049; odds ratio (OR) 9.91, 95% confidence interval (CI) 1.92–51.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE. Significance We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes.

Published
2013

17. Association of TMTC2 with human nonsyndromic sensorineural hearing loss

Author

Runge, C.L., Indap, A., Zhou, Y., Kent, J.W., King, E., Erbe, C.B., Cole, R., Littrell, J., Merath, K., James, R., Rüschendorf, F., Kerschner, J.E., Marth, G., Hübner, N., Göring, H.H.H., Friedland, D.R., Kwok, W.M., and Olivier, M.

Subjects
Cardiovascular and Metabolic Diseases, otorhinolaryngologic diseases
Abstract

IMPORTANCE: Sensorineural hearing loss (SNHL) is commonly caused by conditions that affect cochlear structures or the auditory nerve, and the genes identified as causing SNHL to date only explain a fraction of the overall genetic risk for this debilitating disorder. It is likely that other genes and mutations also cause SNHL. OBJECTIVE: To identify a candidate gene that causes bilateral, symmetric, progressive SNHL in a large multigeneration family of Northern European descent. DESIGN, SETTING, AND PARTICIPANTS: In this prospective genotype and phenotype study performed from January 1, 2006, through April 1, 2016, a 6-generation family of Northern European descent with 19 individuals having reported early-onset hearing loss suggestive of an autosomal dominant inheritance were studied at a tertiary academic medical center. In addition, 179 unrelated adult individuals with SNHL and 186 adult individuals reporting nondeafness were examined. MAIN OUTCOMES AND MEASURES: Sensorineural hearing loss. RESULTS: Nine family members (5 women [55.6%]) provided clinical audiometric and medical records that documented hearing loss. The hearing loss is characterized as bilateral, symmetric, progressive SNHL that reached severe to profound loss in childhood. Audiometric configurations demonstrated a characteristic dip at 1000 to 2000 Hz. All affected family members wear hearing aids or have undergone cochlear implantation. Exome sequencing and linkage and association analyses identified a fully penetrant sequence variant (rs35725509) on chromosome 12q21 (logarithm of odds, 3.3) in the TMTC2 gene region that segregates with SNHL in this family. This gene explains the SNHL occurrence in this family. The variant is also associated with SNHL in a cohort of 363 unrelated individuals (179 patients with confirmed SNHL and 184 controls, P = 7 x 10-4). CONCLUSIONS AND RELEVANCE: A previously uncharacterized gene, TMTC2, has been identified as a candidate for causing progressive SNHL in humans. This finding identifies a novel locus that causes autosomal dominant SNHL and therefore a more detailed understanding of the genetic basis of SNHL. Because TMTC2 has not been previously reported to regulate auditory function, the discovery reveals a potentially new, uncharacterized mechanism of hearing loss.

Published
2016

18. Erratum: Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy (Epilepsia (2013) 54 (256-264) DOI:10.1111/epi.12517)

Author

Møller, R. S., Weber, Y. G., Klitten, L. L., Trucks, H., Muhle, H., Kunz, W. S., Mefford, H. C., Franke, A., Kautza, M., Wolf, P., Dennig, D., Schreiber, S., Rückert, I. -M., Wichmann, H. -E., Ernst, J. P., Schurmann, C., Grabe, H. J., Tommerup, N., Stephani, U., Lerche, H., Hjalgrim, H., Helbig, I., Sander, T., Zimprich, F., Mörzinger, M., Feucht, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Jordanova, A., Kjelgaard, D. B., Lehesjoki, A. -E., Siren, A., Baulac, S., Leguern, E., Von Spiczak, S., Ostertag, P., Leber, M., Leu, C., Toliat, M. R., Nürnberg, P., Hempelmann, A., Rüschendorf, F., Elger, C. E., Kleefuß-Lie, A. A., Surges, R., Gaus, V., Janz, D., Schmitz, B., Klein, K. M., Reif, P. S., Oertel, W. H., Hamer, H. M., Rosenow, F., Becker, F., Marini, C., Guerrini, R., Mei, D., Norci, V., Zara, F., Striano, P., Robbiano, A., Pezzella, M., Bianchi, A., Gambardella, A., Tinuper, P., La Neve, A., Capovilla, G., Vigliano, P., Crichiutti, G., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Giallonardo, M. T., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., Koeleman, B. P. C., De Kovel, C., Lindhout, D., De Haan, G. -J., Ozbeck, U., Bebek, N., Baykan, B., Ozdemir, O., Ugur, S., Kocasoy-Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Yapici, Z., Ozkara, C., Caglayan, H., Yalcin, O., Yalcin, D., Turkdogan, D., Dizdarer, G., Agan, K., Møller, R. S., Weber, Y. G., Klitten, L. L., Trucks, H., Muhle, H., Kunz, W. S., Mefford, H. C., Franke, A., Kautza, M., Wolf, P., Dennig, D., Schreiber, S., Rückert, I. -M., Wichmann, H. -E., Ernst, J. P., Schurmann, C., Grabe, H. J., Tommerup, N., Stephani, U., Lerche, H., Hjalgrim, H., Helbig, I., Sander, T., Zimprich, F., Mörzinger, M., Feucht, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Jordanova, A., Kjelgaard, D. B., Lehesjoki, A. -E., Siren, A., Baulac, S., Leguern, E., Von Spiczak, S., Ostertag, P., Leber, M., Leu, C., Toliat, M. R., Nürnberg, P., Hempelmann, A., Rüschendorf, F., Elger, C. E., Kleefuß-Lie, A. A., Surges, R., Gaus, V., Janz, D., Schmitz, B., Klein, K. M., Reif, P. S., Oertel, W. H., Hamer, H. M., Rosenow, F., Becker, F., Marini, C., Guerrini, R., Mei, D., Norci, V., Zara, F., Striano, P., Robbiano, A., Pezzella, M., Bianchi, A., Gambardella, A., Tinuper, P., La Neve, A., Capovilla, G., Vigliano, P., Crichiutti, G., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Giallonardo, M. T., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., Koeleman, B. P. C., De Kovel, C., Lindhout, D., De Haan, G. -J., Ozbeck, U., Bebek, N., Baykan, B., Ozdemir, O., Ugur, S., Kocasoy-Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Yapici, Z., Ozkara, C., Caglayan, H., Yalcin, O., Yalcin, D., Turkdogan, D., Dizdarer, G., and Agan, K.

Published
2013

19. Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies

Author

EPICURE Consortium, Leu C., de Kovel C. G., Zara F., Striano P., Pezzella M., Robbiano A., Bianchi A., Coppola A., Giallonardo A. T., Beccaria F., Trenité D. K., Lindhout D., Gaus V., Schmitz B., Janz D., Weber Y. G., Becker F., Lerche H., Kleefuss Lie A. A., Hallman K., Kunz W. S., Elger C. E., Muhle H., Stephani U., Møller R. S., Hjalgrim H., Mullen S., Scheffer I. E., Berkovic S. F., Everett K. V., Gardiner M. R., Marini C., Guerrini R., Lehesjoki A. E., Siren A., Nabbout R., Baulac S., Leguern E., Serratosa J. M., Rosenow F., Feucht M., Unterberger I., Covanis A., Suls A., Weckhuysen S., Kaneva R., Caglayan H., Turkdogan D., Baykan B., Bebek N., Ozbek U., Hempelmann A., Schulz H., Rüschendorf F., Trucks H., Nürnberg P., Avanzini G., Koeleman B. P., Sander T., BISULLI, FRANCESCA, TINUPER, PAOLO, YÜCESAN, EMRAH, EPICURE Consortium, Leu C., de Kovel C.G., Zara F., Striano P., Pezzella M., Robbiano A., Bianchi A., Bisulli F., Coppola A., Giallonardo A.T., Beccaria F., Trenité D.K., Lindhout D., Gaus V., Schmitz B., Janz D., Weber Y.G., Becker F., Lerche H., Kleefuss-Lie A.A., Hallman K., Kunz W.S., Elger C.E., Muhle H., Stephani U., Møller R.S., Hjalgrim H., Mullen S., Scheffer I.E., Berkovic S.F., Everett K.V., Gardiner M.R., Marini C., Guerrini R., Lehesjoki A.E., Siren A., Nabbout R., Baulac S., Leguern E., Serratosa J.M., Rosenow F., Feucht M., Unterberger I., Covanis A., Suls A., Weckhuysen S., Kaneva R., Caglayan H., Turkdogan D., Baykan B., Bebek N., Ozbek U., Hempelmann A., Schulz H., Rüschendorf F., Trucks H., Nürnberg P., Avanzini G., Koeleman B.P., Sander T., and Tinuper P.

Subjects
Male, Chromosomes, Human, Pair 13, Genotype, Genetic Linkage, Chromosome Mapping, complex inheritance, Pedigree, genetic generalized epilepsy, myoclonic seizure, Phenotype, Genetic Loci, Chromosomes, Human, Pair 2, Humans, Epilepsy, Generalized, Family, Female, Genetic Predisposition to Disease, linkage analysis, absence seizure, Genome-Wide Association Study
Abstract

PURPOSE: Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure type-related genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively. METHODS: Meta-analysis of three genome-wide linkage datasets was carried out in 379 GGE-multiplex families of European ancestry including 982 relatives with GGEs. To dissect out seizure type-related susceptibility genes, two family subgroups were stratified comprising 235 families with predominantly genetic absence epilepsies (GAEs) and 118 families with an aggregation of juvenile myoclonic epilepsy (JME). To map shared and seizure type-related susceptibility loci, both nonparametric loci (NPL) and parametric linkage analyses were performed for a broad trait model (GGEs) in the entire set of GGE-multiplex families and a narrow trait model (typical absence or myoclonic seizures) in the subgroups of JME and GAE families. KEY FINDINGS: For the entire set of 379 GGE-multiplex families, linkage analysis revealed six loci achieving suggestive evidence for linkage at 1p36.22, 3p14.2, 5q34, 13q12.12, 13q31.3, and 19q13.42. The linkage finding at 5q34 was consistently supported by both NPL and parametric linkage results across all three family groups. A genome-wide significant nonparametric logarithm of odds score of 3.43 was obtained at 2q34 in 118 JME families. Significant parametric linkage to 13q31.3 was found in 235 GAE families assuming recessive inheritance (heterogeneity logarithm of odds = 5.02). SIGNIFICANCE: Our linkage results support an oligogenic predisposition of familial GGE syndromes. The genetic risk factor at 5q34 confers risk to a broad spectrum of familial GGE syndromes, whereas susceptibility loci at 2q34 and 13q31.3 preferentially predispose to myoclonic seizures or absence seizures, respectively. Phenotype- genotype strategies applying narrow trait definitions in phenotypic homogeneous subgroups of families improve the prospects of disentangling the genetic basis of common familial GGE syndromes.

Published
2012

20. Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies

Author

Leu C, de Kovel CG, Zara F, Striano P, Pezzella M, Robbiano A, Bianchi A, Bisulli F, Coppola A, Giallonardo AT, Beccaria F, Trenité DK, Lindhout D, Gaus V, Schmitz B, Janz D, Weber YG, Becker F, Lerche H, Kleefuss Lie AA, Hallman K, Kunz WS, Elger CE, Muhle H, Stephani U, Møller RS, Hjalgrim H, Mullen S, Scheffer IE, Berkovic SF, Everett KV, Gardiner MR, Marini C, Guerrini R, Lehesjoki AE, Siren A, Nabbout R, Baulac S, Leguern E, Serratosa JM, Rosenow F, Feucht M, Unterberger I, Covanis A, Suls A, Weckhuysen S, Kaneva R, Caglayan H, Turkdogan D, Baykan B, Bebek N, Ozbek U, Hempelmann A, Schulz H, Rüschendorf F, Trucks H, Nürnberg P, Avanzini G, Koeleman BP, Sander T, EPICURE Consortium, COPPOLA, ANTONIETTA, DEL GIUDICE, ENNIO, Leu, C, de Kovel, Cg, Zara, F, Striano, P, Pezzella, M, Robbiano, A, Bianchi, A, Bisulli, F, Coppola, A, Giallonardo, At, Beccaria, F, Trenité, Dk, Lindhout, D, Gaus, V, Schmitz, B, Janz, D, Weber, Yg, Becker, F, Lerche, H, Kleefuss Lie, Aa, Hallman, K, Kunz, W, Elger, Ce, Muhle, H, Stephani, U, Møller, R, Hjalgrim, H, Mullen, S, Scheffer, Ie, Berkovic, Sf, Everett, Kv, Gardiner, Mr, Marini, C, Guerrini, R, Lehesjoki, Ae, Siren, A, Nabbout, R, Baulac, S, Leguern, E, Serratosa, Jm, Rosenow, F, Feucht, M, Unterberger, I, Covanis, A, Suls, A, Weckhuysen, S, Kaneva, R, Caglayan, H, Turkdogan, D, Baykan, B, Bebek, N, Ozbek, U, Hempelmann, A, Schulz, H, Rüschendorf, F, Trucks, H, Nürnberg, P, Avanzini, G, Koeleman, Bp, Sander, T, Epicure, Consortium, DEL GIUDICE, Ennio, and Coppola, Antonietta

Published
2012

21. Meta-analysis identifies seven susceptibility loci involved in the atopic March

Author

Marenholz, I, Esparza-Gordillo, J, Rüschendorf, F, Bauerfeind, A, Strachan, DP, Spycher, BD, Baurecht, H, Margaritte-Jeannin, P, Sääf, A, Kerkhof, M, Ege, M, Baltic, S, Matheson, MC, Li, J, Michel, S, Ang, WQ, McArdle, W, Arnold, A, Homuth, G, Demenais, F, Bouzigon, E, Söderhäll, C, Pershagen, G, De Jongste, JC, Postma, DS, Braun-Fahrländer, C, Horak, E, Ogorodova, LM, Puzyrev, VP, Bragina, EY, Hudson, TJ, Morin, C, Duffy, DL, Marks, GB, Robertson, CF, Montgomery, GW, Musk, B, Thompson, PJ, Martin, NG, James, A, Sleiman, P, Toskala, E, Rodriguez, E, Fölster-Holst, R, Franke, A, Lieb, W, Gieger, C, Heinzmann, A, Rietschel, E, Keil, T, Cichon, S, Nöthen, MM, Pennell, CE, Sly, PD, Schmidt, CO, Matanovic, A, Schneider, V, Heinig, M, Hübner, N, Holt, PG, Lau, S, Kabesch, M, Weidinger, S, Hakonarson, H, Ferreira, MAR, Laprise, C, Freidin, MB, Genuneit, J, Koppelman, GH, Melén, E, Dizier, MH, Henderson, AJ, Lee, YA, Marenholz, I, Esparza-Gordillo, J, Rüschendorf, F, Bauerfeind, A, Strachan, DP, Spycher, BD, Baurecht, H, Margaritte-Jeannin, P, Sääf, A, Kerkhof, M, Ege, M, Baltic, S, Matheson, MC, Li, J, Michel, S, Ang, WQ, McArdle, W, Arnold, A, Homuth, G, Demenais, F, Bouzigon, E, Söderhäll, C, Pershagen, G, De Jongste, JC, Postma, DS, Braun-Fahrländer, C, Horak, E, Ogorodova, LM, Puzyrev, VP, Bragina, EY, Hudson, TJ, Morin, C, Duffy, DL, Marks, GB, Robertson, CF, Montgomery, GW, Musk, B, Thompson, PJ, Martin, NG, James, A, Sleiman, P, Toskala, E, Rodriguez, E, Fölster-Holst, R, Franke, A, Lieb, W, Gieger, C, Heinzmann, A, Rietschel, E, Keil, T, Cichon, S, Nöthen, MM, Pennell, CE, Sly, PD, Schmidt, CO, Matanovic, A, Schneider, V, Heinig, M, Hübner, N, Holt, PG, Lau, S, Kabesch, M, Weidinger, S, Hakonarson, H, Ferreira, MAR, Laprise, C, Freidin, MB, Genuneit, J, Koppelman, GH, Melén, E, Dizier, MH, Henderson, AJ, and Lee, YA

Abstract

Eczema often precedes the development of asthma in a disease course called the a € atopic marcha €. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10 a'8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10 a'9). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.

Published
2015

22. Meta-analysis identifies seven susceptibility loci involved in the atopic March

Author

Marenholz, I. (Ingo), Esparza-Gordillo, J. (Jorge), Rüschendorf, F. (Franz), Bauerfeind, A. (Anja), Strachan, D.P. (David P.), Spycher, B.D. (Ben D.), Baurecht, H. (Hansjörg), Margaritte-Jeannin, P. (Patricia), Sääf, A. (Annika), Kerkhof, M. (Marjan), Ege, M. (Markus), Baltic, S. (Svetlana), Matheson, J., Li, J. (Jin), Michel, S. (Sven), Ang, W.Q. (Wei Q.), McArdle, W.L. (Wendy), Homuth, G. (Georg), Demenais, F. (Florence), Bouzigon, E. (Emmanuelle), Söderhäll, C. (Cilla), Pershagen, G. (Göran), Jongste, J.C. (Johan) de, Postma, D.S. (Dirkje), Braun-Fahrländer, C. (Charlotte), Horak, E. (Elisabeth), Ogorodova, L.M. (Ludmila M.), Puzyrev, V.P. (Valery P.), Bragina, E.Y. (Elena Yu), Hudson, T.J. (Thomas), Morin, C. (Charles), Duffy, D.L. (David), Marks, G.B. (Guy B.), Robertson, C., Montgomery, G.W. (Grant), Musk, A.W. (Arthur), Thompson, P.J. (Philip), Martin, N.G. (Nicholas), James, A.L. (Alan), Sleiman, P.M.A. (Patrick), Toskala, E. (Elina), Rodríguez, P.M., Fölster-Holst, R. (R.), Franke, A. (Andre), Lieb, W. (Wolfgang), Gieger, C. (Christian), Heinzmann, A. (Andrea), Rietschel, E. (Ernst), Keil, M. (Mark), Cichon, S. (Sven), Nöthen, M.M. (Markus M.), Pennell, C.E. (Craig), Sly, P.D., Schmidt, C.O. (Carsten Oliver), Matanovic, A. (Anja), Schneider, V. (Valentin), Heinig, M. (Matthias), Hübner, N. (Norbert), Holt, P.G. (Patrick), Lau, S. (Susanne), Kabesch, M. (Michael), Weidinger, S. (Stefan), Hakonarson, H. (Hakon), Ferreira, M.A. (Manuel), Laprise, C. (Catherine), Freidin, M.B. (M.), Genuneit, J. (Jon), Koppelman, G.H. (Gerard), Melén, E. (Erik), Dizier, M.-H., Arnold, A.M. (Alice), Henderson, A.J. (A. John), Lee, Y.-A. (Young-Ae), Marenholz, I. (Ingo), Esparza-Gordillo, J. (Jorge), Rüschendorf, F. (Franz), Bauerfeind, A. (Anja), Strachan, D.P. (David P.), Spycher, B.D. (Ben D.), Baurecht, H. (Hansjörg), Margaritte-Jeannin, P. (Patricia), Sääf, A. (Annika), Kerkhof, M. (Marjan), Ege, M. (Markus), Baltic, S. (Svetlana), Matheson, J., Li, J. (Jin), Michel, S. (Sven), Ang, W.Q. (Wei Q.), McArdle, W.L. (Wendy), Homuth, G. (Georg), Demenais, F. (Florence), Bouzigon, E. (Emmanuelle), Söderhäll, C. (Cilla), Pershagen, G. (Göran), Jongste, J.C. (Johan) de, Postma, D.S. (Dirkje), Braun-Fahrländer, C. (Charlotte), Horak, E. (Elisabeth), Ogorodova, L.M. (Ludmila M.), Puzyrev, V.P. (Valery P.), Bragina, E.Y. (Elena Yu), Hudson, T.J. (Thomas), Morin, C. (Charles), Duffy, D.L. (David), Marks, G.B. (Guy B.), Robertson, C., Montgomery, G.W. (Grant), Musk, A.W. (Arthur), Thompson, P.J. (Philip), Martin, N.G. (Nicholas), James, A.L. (Alan), Sleiman, P.M.A. (Patrick), Toskala, E. (Elina), Rodríguez, P.M., Fölster-Holst, R. (R.), Franke, A. (Andre), Lieb, W. (Wolfgang), Gieger, C. (Christian), Heinzmann, A. (Andrea), Rietschel, E. (Ernst), Keil, M. (Mark), Cichon, S. (Sven), Nöthen, M.M. (Markus M.), Pennell, C.E. (Craig), Sly, P.D., Schmidt, C.O. (Carsten Oliver), Matanovic, A. (Anja), Schneider, V. (Valentin), Heinig, M. (Matthias), Hübner, N. (Norbert), Holt, P.G. (Patrick), Lau, S. (Susanne), Kabesch, M. (Michael), Weidinger, S. (Stefan), Hakonarson, H. (Hakon), Ferreira, M.A. (Manuel), Laprise, C. (Catherine), Freidin, M.B. (M.), Genuneit, J. (Jon), Koppelman, G.H. (Gerard), Melén, E. (Erik), Dizier, M.-H., Arnold, A.M. (Alice), Henderson, A.J. (A. John), and Lee, Y.-A. (Young-Ae)

Abstract

Eczema often precedes the development of asthma in a disease course called the a 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10 a'8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10 a'9). Additional susceptibility loci identified a

Published
2015
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23. Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1,2q22.3 and 17q21.32

Author

Steffens, M., Leu, C., Ruppert, A., Zara, F., Striano, P., Robbiano, A., Capovilla, G., Tinuper, P., Gambardella, A., Bianchi, A., La neve, A., Crichiutti, G., de kovel, C. G., Trenité, D. K. -N., de haan, G., Lindhout, D., Gaus, V., Schmitz, B., Janz, D., Weber, Y. G., Becker, F., Lerche, H., Steinhoff, B. J., Kleefuß-Lie, A. A., Kunz, W. S., Surges, R., Elger, C. E., Muhle, H., Von spiczak, S., Ostertag, P., Helbig, I., Stephani, U., Møller, R. S., Hjalgrim, H., Dibbens, L. M., Bellows, S., Oliver, K., Mullen, S., Scheffer, I. E., Berkovic, S. F., Everett, K. V., Gardiner, M. R., Marini, Chiara, Guerrini, R., Lehesjoki, A., Siren, A., Guipponi, M., Malafosse, A., Thomas, P., Nabbout, R., Baulac, S., Leguern, E., Guerrero, R., Serratosa, J. M., Reif, P. S., Rosenow, F., Mörzinger, M., Feucht, M., Zimprich, F., Kapser, C., Schankin, C. J., Suls, A., Smets, K., De jonghe, P., Jordanova, A., Caglayan, H., Yapici, Z., Yalcin, D. A., Baykan, B., Bebek, N., Ozbek, U., Gieger, C., Wichmann, H., Balschun, T., Ellinghaus, D., Franke, A., Meesters, C., Becker, T., Wienker, T. F., Hempelmann, A., Schulz, H., Rüschendorf, F., Leber, M., Pauck, S. M., Trucks, H., Toliat, M. R., Nürnberg, P., Avanzini, G., Koeleman, B. P., Sander, T., Weckhuysen, S., Claes, L., Deprez, L., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Lehesjoki, A. -E., von Spiczak, S., Martin Klein, K., Oertel, W. H., Hamer, H. M., Marini, C., Mei, D., Norci, V., Pezzella, M., La Neve, A., Vigliano, P., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Egeo, G., Teresa Giallonardo, M., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., de Haan, G. -J., Giraldez, B. G., Ozbeck, U., Ozdemir, O., Ugur, S., Kocasoy-Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Ozkara, C., Yalcin, O., Turkdogan, D., Dizdarer, G., Agan, K., Steffens, Michael, Leu, Costin, Ruppert, Ann-Kathrin, Zara, Frederico, Dibbens, Leanne Michelle, Sander, Thomas, EPICURE Consortium, Epicure, Consortium, DEL GIUDICE, Ennio, Steffens, M, Leu, C, Ruppert, Ak, Zara, F, Striano, P, Robbiano, A., Coppola, Antonietta, E. P. I. C. U. R. E. Consortium, E. M. I.Net Consortium, M. Steffen, C. Leu, A. Ruppert, F. Zara, P. Striano, A. Robbiano, G. Capovilla, P. Tinuper, A. Gambardella, A. Bianchi, A. L. Neve, G. Crichiutti, C. G. F, D. K. Trenité, G. d. Haan, D. Lindhout, V. Gau, B. Schmitz, D. Janz, Y. G. Weber, F. Becker, H. Lerche, B. J. Steinhoff, A. A. Kleefuß-Lie, W. S. Kunz, R. Surge, C. E. Elger, H. Muhle, S. v. Spiczak, P. Ostertag, I. Helbig, U. Stephani, R. S. Møller, H. Hjalgrim, L. M. Dibben, S. Bellow, K. Oliver, S. Mullen, I. E. Scheffer, S. F. Berkovic, K. V. Everett, M. R. Gardiner, C. Marini, R. Guerrini, A. Lehesjoki, A. Siren, M. Guipponi, A. Malafosse, P. Thoma, R. Nabbout, S. Baulac, E. Leguern, R. Guerrero, J. M. Serratosa, P. S. Reif, F. Rosenow, M. Mörzinger, M. Feucht, F. Zimprich, C. Kapser, C. J. Schankin, A. Sul, K. Smet, P. D. Jonghe, A. Jordanova, H. Caglayan, Z. Yapici, D. A. Yalcin, B. Baykan, N. Bebek, U. Ozbek, C. Gieger, H. Wichmann, T. Balschun, D. Ellinghau, A. Franke, C. Meester, T. Becker, T. F. Wienker, A. Hempelmann, H. Schulz, F. Rüschendorf, M. Leber, S. M. Pauck, H. Truck, M. R. Toliat, P. Nürnberg, G. Avanzini, B. P. C, and T. Sander

Subjects
Candidate gene, Juvenile, Genome-wide association study, Alleles, Epilepsy, ZEB2 protein, human, VRK2 protein, human, 0302 clinical medicine, genetics [Genetic Predisposition to Disease], genetics, Humans, Myoclonic Epilepsy, genetics [Epilepsy, Generalized], SCN1A protein, human, Genetics (clinical), Genetics, 0303 health sciences, genetics [Epilepsy, Absence], Myoclonic Epilepsy, Juvenile, genetics, Genetic Predisposition to Disease, General Medicine, Protein-Serine-Threonine Kinases, 3. Good health, Chemistry, Absence, genetics, Epilepsy, genetics [Myoclonic Epilepsy, Juvenile], Epilepsy, Generalized, genetics [Receptor, Muscarinic M3], genetics, NAV1.1 Voltage-Gated Sodium Channel, genetics [Homeodomain Proteins], Single-nucleotide polymorphism, genetics [NAV1.1 Voltage-Gated Sodium Channel], Protein Serine-Threonine Kinases, Biology, genetics [Protein-Serine-Threonine Kinases], 03 medical and health sciences, ddc:570, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, genetics, Repressor Protein, Allele, Molecular Biology, Alleles, Zinc Finger E-box Binding Homeobox 2, 030304 developmental biology, Homeodomain Proteins, Receptor, Muscarinic M3, genetics, Protein-Serine-Threonine Kinase, genetics, Receptor, Generalized, genetics, Genome-Wide Association Study, Homeodomain Protein, Heritability, medicine.disease, NAV1.1 Voltage-Gated Sodium Channel, Repressor Proteins, genetics [Repressor Proteins], Muscarinic M3, Epilepsy, Absence, Myoclonic epilepsy, Human medicine, Juvenile myoclonic epilepsy, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3\% and account for 20-30\% of all epilepsies. Despite their high heritability of 80\%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.

Published
2012

24. Congenital myopathy Ehlers-Danlos overlap syndrome caused by the deficiency of an enzyme involved in protein folding in the endoplasmic reticulum: identification and characterization of a novel disorder

Author

Fauth, C., Baumann, M., Giunta, C., Krabichler, B., Rüschendorf, F., Bönnemann, C. G., Bittner, R. E., Colombi, Marina, Zoppi, Nicoletta, Quijano Roy, S., Romero, N. B., Carlier, R. Y., Muntoni, F., Cirak, S., Schreiber, G., Amberger, A., Deutschmann, A., Straub, V., Rohrbach, M., Rostásy, K., Karall, D., and Zschockej

Subjects
Myopathy, Ehlers-Danlos syndrome
Published
2011

29. Refinement of the gene locus for autosomal dominant medullary cystic kidney disease type 1 (MCKD1) and construction of a physical and partial transcriptional map of the region

Author

Rüschendorf, F., Fuchshuber, A., Kroiss, S., Karle, S., Berthold, S., Huck, K., Burton, C., Rahman, N., Koptides, Michael, Constantinou-Deltas, Constantinos D., Otto, E., Feest, T., Hildebrandt, F., and Constantinou-Deltas, Constantinos D. [0000-0001-5549-9169]

Subjects
Yeast artificial chromosome, Male, marker gene, Candidate gene, haplotype, gene locus, Transcription, Genetic, Genetic Linkage, kidney disease, Locus (genetics), Biology, Medullary cystic kidney disease, pedigree analysis, autosomal dominant disorder, Contig Mapping, medullary sponge kidney, Gene mapping, Genetics, medicine, Humans, controlled study, human, chromosome, Bacteria (microorganisms), Family Health, Bacterial artificial chromosome, clinical article, Contig, Gene map, adult, article, Linkage (Genetics), DNA, gene mapping, medicine.disease, Polycystic Kidney, Autosomal Dominant, Physical Chromosome Mapping, kidney failure, Pedigree, priority journal, Haplotypes, Chromosomes, Human, Pair 1, Female, Microsatellite Repeats
Abstract

Autosomal dominant medullary cystic kidney disease (MCKD) is an adult onset tubulointerstitial nephropathy that leads to salt wasting and end-stage renal failure. A gene locus (MCKD1) has been mapped on chromosome 1q21. Here we report on a large MCKD1 family of British origin linked to the MCKD1 locus. Haplotype analysis performed with markers spanning the previously reported critical MCKD1 region allowed for the refinement of this interval to 4 cM by definition of D1S305 as a new proximal flanking marker. Furthermore, we constructed a yeast artificial chromosome, P1-related artificial chromosome, and bacterial artificial chromosome contig of this region, which is only sparsely covered by the Human Genome Sequencing Project. This enabled us to map numerous expressed sequence tags within the critical interval. This physical and partial transcriptional map of the MCKD1 region is a powerful tool for the identification of positional and functional candidate genes for MCKD1 and will help to identify the disease-causing gene. © 2001 Academic Press. 72 278 284 Cited By :23

Published
2001

30. A genetic basis for mechanosensory traits in humans.

Author

Frenzel, H, Bohlender, J, Pinsker, K, Wohlleben, B, Tank, J, Lechner, S G, Schiska, D, Jaijo, T, Rüschendorf, F, Saar, K, Jordan, J, Millán, J M, Gross, M, Lewin, G R, Frenzel, H, Bohlender, J, Pinsker, K, Wohlleben, B, Tank, J, Lechner, S G, Schiska, D, Jaijo, T, Rüschendorf, F, Saar, K, Jordan, J, Millán, J M, Gross, M, and Lewin, G R

Abstract

In all vertebrates hearing and touch represent two distinct sensory systems that both rely on the transformation of mechanical force into electrical signals. There is an extensive literature describing single gene mutations in humans that cause hearing impairment, but there are essentially none for touch. Here we first asked if touch sensitivity is a heritable trait and second whether there are common genes that influence different mechanosensory senses like hearing and touch in humans. Using a classical twin study design we demonstrate that touch sensitivity and touch acuity are highly heritable traits. Quantitative phenotypic measures of different mechanosensory systems revealed significant correlations between touch and hearing acuity in a healthy human population. Thus mutations in genes causing deafness genes could conceivably negatively influence touch sensitivity. In agreement with this hypothesis we found that a proportion of a cohort of congenitally deaf young adults display significantly impaired measures of touch sensitivity compared to controls. In contrast, blind individuals showed enhanced, not diminished touch acuity. Finally, by examining a cohort of patients with Usher syndrome, a genetically well-characterized deaf-blindness syndrome, we could show that recessive pathogenic mutations in the USH2A gene influence touch acuity. Control Usher syndrome cohorts lacking demonstrable pathogenic USH2A mutations showed no impairment in touch acuity. Our study thus provides comprehensive evidence that there are common genetic elements that contribute to touch and hearing and has identified one of these genes as USH2A.

Published
2012

32. Association scan of the novel psoriasis susceptibility region on chromosome 19 : evidence for both susceptible and protective loci

Author

Hensen, P, Windemuth, C, Hüffmeier, U, Rüschendorf, F, Stadelmann, A, Hoppe, V, Fenneker, D, Ständer, M, Schmitt-Egenolf, Marcus, Wienker, TF, Traupe, H, Reis, A, Hensen, P, Windemuth, C, Hüffmeier, U, Rüschendorf, F, Stadelmann, A, Hoppe, V, Fenneker, D, Ständer, M, Schmitt-Egenolf, Marcus, Wienker, TF, Traupe, H, and Reis, A

Abstract

To follow up the novel psoriasis susceptibility region on chromosome 19 (PSORS6), we performed an association scan for psoriasis vulgaris using 45 evenly spaced DNA microsatellite markers. For this study, a new independent sample of 210 nuclear psoriasis families (trio design) from Northern Germany was recruited. We used the family based association test (FBAT) for an association scan over the chromosome 19 region encompassing 50.8 cM. We obtained a positive association for the markers D19S922 (allele 5, P = 0.008) and D19S916 (allele 13, P = 0.016), which correspond to the peak of the region identified in a previously performed scan. We identified two novel regions by a single marker, each showing negative association at D19S917 on 19p13.1 (allele 8, P = 0.0034) and at D19S425 (allele 9, P = 0.0005), compatible with the hypothesis of protective loci. These two novel regions were explored in more detail using novel microsatellite markers at an average distance of 100 kb. A separate analysis distinguishing between familial (n = 137) and sporadic (n = 73) psoriasis families showed that the familial trios contribute strongly in the region around D19S425 (P = 0.004), while the comparably small subset of 73 sporadic trios has a stronger effect at the locus around D19S917 (P = 0.026). These studies confirm the existence of a psoriasis susceptibility locus on chromosome 19 and give first evidence for the existence of both susceptible and protective loci in this region. Analysis of a dense marker set from these refined regions will eventually allow identification of the underlying susceptibility alleles.

Published
2003
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33. Interleukin-10 promoter polymorphism IL10.G and familial early onset psoriasis

Author

Hensen, P, Asadullah, K, Windemuth, C, Rüschendorf, F, Hüffmeier, U, Ständer, M, Schmitt-Egenolf, Marcus, Wienker, TF, Reis, A, Traupe, H, Hensen, P, Asadullah, K, Windemuth, C, Rüschendorf, F, Hüffmeier, U, Ständer, M, Schmitt-Egenolf, Marcus, Wienker, TF, Reis, A, and Traupe, H

Abstract

BACKGROUND: The anti-inflammatory cytokine interleukin (IL)-10 is considered to play a major role in the pathophysiology of psoriasis, which is characterized by an IL-10 deficiency. Systemic administration of IL-10 has been shown to be an effective therapy for psoriasis. The IL-10 promoter region contains a highly polymorphic microsatellite (IL10.G) and in a recent case-control study the IL10.G13 (144 bp) allele was found to be associated with familial early onset psoriasis (type 1 psoriasis) having a susceptible effect. OBJECTIVES: As it is essential in multifactorial diseases to replicate findings before definite conclusions can be drawn, we decided to perform a follow-up study and to follow a genetic approach analysing allele transmission in families with a positive family history of psoriasis. METHODS: We studied 137 nuclear families (trio-design) comprising 456 individuals and genotyped the IL10.G marker. For comparison we also genotyped the microsatellite tn62 as a reference marker of the major psoriasis susceptibility locus on chromosome 6p21 (PSORS1). In the present study allele transmission was evaluated using the family-based association test (FBAT) and GENEHUNTER 2.0 based on the transmission/disequilibrium test. RESULTS: The G13 allele (144 bp) had a frequency of 24%, was present in 88 families and clearly showed an even transmission (FBAT, P = 0.753). In contrast, allele 3 (IL10.G9) (136 bp) had a frequency of 39%, was present in 110 families and was transmitted in 43 trios and remained untransmitted in 67 trios (FBAT, P = 0.026), thus showing preferential nontransmission. For the HLA-linked tn62-marker we obtained a P-value of 0.00027 for allele 4 in the same study group. CONCLUSIONS: In conclusion, we failed to confirm the susceptible effect of the G13 allele, but provide the first data for a protective effect of allele 3 (IL10.G9) for familial psoriasis. Our results suggest that the IL10.G polymorphism is not a major locus, but acts as a minor locus.

Published
2003
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36. Genomewide scan in german families reveals evidence for a novel psoriasis-susceptibility locus on chromosome 19p13

Author

Lee, YA, Rüschendorf, F, Windemuth, C, Schmitt-Egenolf, Marcus, Stadelmann, A, Nürnberg, G, Ständer, M, Wienker, TF, Reis, A, Traupe, H, Lee, YA, Rüschendorf, F, Windemuth, C, Schmitt-Egenolf, Marcus, Stadelmann, A, Nürnberg, G, Ständer, M, Wienker, TF, Reis, A, and Traupe, H

Abstract

Psoriasis is a common chronic inflammatory skin disease with a strong genetic component. Few psoriasis-susceptibility loci have been reported, and only two have been confirmed in independent data sets. This article reports results of a genomewide scan that was performed, using 370 microsatellite markers, for psoriasis-susceptibility loci in 32 German extended families, comprising 162 affected and 195 unaffected individuals. Nonparametric linkage analysis of all families provided strong evidence for a novel psoriasis-susceptibility locus on chromosome 19p (Zlr=3.50; P=.0002). Parametric analysis revealed a heterogeneity LOD score of 4.06, corresponding to a genomewide significance level of.037, under the assumption of a recessive model with high disease-allele frequency and 66% as the proportion of linked families. This study confirms linkage of psoriasis to the HLA region on chromosome 6p and suggests additional regions on chromosomes 8q and 21q for further investigations.

Published
2000
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40. Limb Mammary syndrome: a new genetic disorder with mammary hypoplasia, ectrodactyly, and other hand/foot anomalies maps to human chromosome 3q27.

Author

Bokhoven, J.H.L.M. van, Jung, M., Smits, A.P.T., Beersum, S.E.C. van, Rüschendorf, F., Steensel, M.A.M. van, Veenstra, M., Tuerlings, J.H.A.M., Mariman, E.C.M., Brunner, H.G., Wienker, T.F., Reis, A., Ropers, H.H., Hamel, B.C.J., Bokhoven, J.H.L.M. van, Jung, M., Smits, A.P.T., Beersum, S.E.C. van, Rüschendorf, F., Steensel, M.A.M. van, Veenstra, M., Tuerlings, J.H.A.M., Mariman, E.C.M., Brunner, H.G., Wienker, T.F., Reis, A., Ropers, H.H., and Hamel, B.C.J.

Abstract

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Published
1999

42. Refinement of the Gene Locus for Autosomal Dominant Medullary Cystic Kidney Disease Type 1 (MCKD1) and Construction of a Physical and Partial Transcriptional Map of the Region

Author

Fuchshuber, A., primary, Kroiss, S., additional, Karle, S., additional, Berthold, S., additional, Huck, K., additional, Burton, C., additional, Rahman, N., additional, Koptides, M., additional, Deltas, C., additional, Otto, E., additional, Rüschendorf, F., additional, Feest, T., additional, and Hildebrandt, F., additional

Published
2001
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44. Evidence of further genetic heterogeneity in autosomal dominant medullary cystic kidney disease.

Author

Kroiss, S, Huck, K, Berthold, S, Rüschendorf, F, Scolari, F, Caridi, G, Ghiggeri, G M, Hildebrandt, F, and Fuchshuber, A

Abstract

Autosomal dominant medullary cystic kidney disease is a genetically heterogeneous nephropathy with clinical and morphological features similar to recessively inherited juvenile nephronophthisis. Recently, a second gene locus on chromosome 16p12, MCKD2 has been mapped [1] in addition to the known locus on chromosome 1q21 (MCKD1) [2]. In a previous study we have excluded linkage for three caucasian families to the MCKD1 locus [3].

Published
2000
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46. Phenotypic and genetic heterogeneity in a genome-wide linkage study of asthma families

Author

Schuster Antje, Keller Angela, Kelber Julika, Jellouschek Heidemarie, Friedrichs Frank, Bulle Dieter, Loesgen Sabine, Lee Young-Ae, Seidel Corinna, Altmüller Janine, Silbermann Michael, Wahlen Wolfgang, Wolff Peter, Schlenvoigt Gerhard, Rüschendorf Franz, Nürnberg Peter, and Wjst Matthias

Subjects
Diseases of the respiratory system, RC705-779
Abstract

Abstract Background Asthma is a complex genetic disease with more than 20 genome-wide scans conducted so far. Regions on almost every chromosome have been linked to asthma and several genes have been associated. However, most of these associations are weak and are still awaiting replication. Methods In this study, we conducted a second-stage genome-wide scan with 408 microsatellite markers on 201 asthma-affected sib pair families and defined clinical subgroups to identify phenotype-genotype relations. Results The lowest P value for asthma in the total sample was 0.003 on chromosome 11, while several of the clinical subsets reached lower significance levels than in the overall sample. Suggestive evidence for linkage (p = 0.0007) was found for total IgE on chromosomes 1, 7 and again on chromosome 11, as well as for HDM asthma on chromosome 12. Weaker linkage signals could be found on chromosomes 4 and 5 for early onset and HDM, and, newly described, on chromosome 2 for severe asthma and on chromosome 9 for hay fever. Conclusions This phenotypic dissection underlines the importance of detailed clinical characterisations and the extreme genetic heterogeneity of asthma.

Published
2005
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47. Corrigendum: Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause severe childhood-onset retinal dystrophy.

Author

Janecke, A. R., Thompson, D. A., Utermann, G., Becker, C., Hübner, C. A., Schmid, E., McHenry, C. L., Nair, A. R., Rüschendorf, F., Heckenlively, J., Wissinger, B., Nürnberg, P., and Gal, A.

Subjects
DEHYDROGENASES
Abstract

Presents a correction to the article "Mutations in RDH12 Encoding a Photoreceptor Cell Retinol Dehydrogenase Cause Severe Childhood-Onset Retinal Dystrophy," previously published in the 2004 edition of "Nature Genetics."

Published
2004
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48. Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function.

Author

Lin SJ, Vona B, Porter HM, Izadi M, Huang K, Lacassie Y, Rosenfeld JA, Khan S, Petree C, Ali TA, Muhammad N, Khan SA, Muhammad N, Liu P, Haymon ML, Rüschendorf F, Kong IK, Schnapp L, Shur N, Chorich L, Layman L, Haaf T, Pourkarimi E, Kim HG, and Varshney GK

Subjects
Exons, Humans, Mutation, Pedigree, RNA, Transfer genetics, Syndrome, Amino Acyl-tRNA Synthetases genetics, Charcot-Marie-Tooth Disease genetics, Tryptophan-tRNA Ligase genetics
Abstract

Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for faithful assignment of amino acids to their cognate tRNA. Variants in ARS genes are frequently associated with clinically heterogeneous phenotypes in humans and follow both autosomal dominant or recessive inheritance patterns in many instances. Variants in tryptophanyl-tRNA synthetase 1 (WARS1) cause autosomal dominantly inherited distal hereditary motor neuropathy and Charcot-Marie-Tooth disease. Presently, only one family with biallelic WARS1 variants has been described. We present three affected individuals from two families with biallelic variants (p.Met1? and p.(Asp419Asn)) in WARS1, showing varying severities of developmental delay and intellectual disability. Hearing impairment and microcephaly, as well as abnormalities of the brain, skeletal system, movement/gait, and behavior were variable features. Phenotyping of knocked down wars-1 in a Caenorhabditis elegans model showed depletion is associated with defects in germ cell development. A wars1 knockout vertebrate model recapitulates the human clinical phenotypes, confirms variant pathogenicity, and uncovers evidence implicating the p.Met1? variant as potentially impacting an exon critical for normal hearing. Together, our findings provide consolidating evidence for biallelic disruption of WARS1 as causal for an autosomal recessive neurodevelopmental syndrome and present a vertebrate model that recapitulates key phenotypes observed in patients., (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)

Published
2022
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49. Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4.

Author

Grosche S, Marenholz I, Esparza-Gordillo J, Arnau-Soler A, Pairo-Castineira E, Rüschendorf F, Ahluwalia TS, Almqvist C, Arnold A, Baurecht H, Bisgaard H, Bønnelykke K, Brown SJ, Bustamante M, Curtin JA, Custovic A, Dharmage SC, Esplugues A, Falchi M, Fernandez-Orth D, Ferreira MAR, Franke A, Gerdes S, Gieger C, Hakonarson H, Holt PG, Homuth G, Hubner N, Hysi PG, Jarvelin MR, Karlsson R, Koppelman GH, Lau S, Lutz M, Magnusson PKE, Marks GB, Müller-Nurasyid M, Nöthen MM, Paternoster L, Pennell CE, Peters A, Rawlik K, Robertson CF, Rodriguez E, Sebert S, Simpson A, Sleiman PMA, Standl M, Stölzl D, Strauch K, Szwajda A, Tenesa A, Thompson PJ, Ullemar V, Visconti A, Vonk JM, Wang CA, Weidinger S, Wielscher M, Worth CL, Xu CJ, and Lee YA

Subjects
Cytokine Receptor Common beta Subunit, Dual Specificity Phosphatase 1 chemistry, Dual Specificity Phosphatase 1 metabolism, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Matrix Attachment Region Binding Proteins, Polymorphism, Single Nucleotide, Rare Diseases genetics, Receptor, Notch4 chemistry, Receptor, Notch4 metabolism, Sodium-Hydrogen Exchangers chemistry, Sodium-Hydrogen Exchangers metabolism, Dual Specificity Phosphatase 1 genetics, Eczema diagnosis, Eczema genetics, Receptor, Notch4 genetics, Sodium-Hydrogen Exchangers genetics
Abstract

Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema., (© 2021. The Author(s).)

Published
2021
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50. A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans.

Author

Vona B, Mazaheri N, Lin SJ, Dunbar LA, Maroofian R, Azaiez H, Booth KT, Vitry S, Rad A, Rüschendorf F, Varshney P, Fowler B, Beetz C, Alagramam KN, Murphy D, Shariati G, Sedaghat A, Houlden H, Petree C, VijayKumar S, Smith RJH, Haaf T, El-Amraoui A, Bowl MR, Varshney GK, and Galehdari H

Subjects
Adult, Alleles, Animals, Base Sequence, Chromosome Mapping, Consanguinity, Female, Gene Expression, Genes, Recessive, Hair Cells, Auditory, Inner pathology, Hearing Loss, Sensorineural metabolism, Hearing Loss, Sensorineural pathology, Humans, Male, Membrane Proteins deficiency, Mice, Pedigree, Tetraspanins deficiency, Exome Sequencing, Zebrafish, Amino Acid Substitution, Chromosomes, Human, Pair 4 chemistry, Hair Cells, Auditory, Inner metabolism, Hearing Loss, Sensorineural genetics, Membrane Proteins genetics, Point Mutation, Tetraspanins genetics
Abstract

Deafness, the most frequent sensory deficit in humans, is extremely heterogeneous with hundreds of genes involved. Clinical and genetic analyses of an extended consanguineous family with pre-lingual, moderate-to-profound autosomal recessive sensorineural hearing loss, allowed us to identify CLRN2, encoding a tetraspan protein, as a new deafness gene. Homozygosity mapping followed by exome sequencing identified a 14.96 Mb locus on chromosome 4p15.32p15.1 containing a likely pathogenic missense variant in CLRN2 (c.494C > A, NM_001079827.2) segregating with the disease. Using in vitro RNA splicing analysis, we show that the CLRN2 c.494C > A variant leads to two events: (1) the substitution of a highly conserved threonine (uncharged amino acid) to lysine (charged amino acid) at position 165, p.(Thr165Lys), and (2) aberrant splicing, with the retention of intron 2 resulting in a stop codon after 26 additional amino acids, p.(Gly146Lysfs*26). Expression studies and phenotyping of newly produced zebrafish and mouse models deficient for clarin 2 further confirm that clarin 2, expressed in the inner ear hair cells, is essential for normal organization and maintenance of the auditory hair bundles, and for hearing function. Together, our findings identify CLRN2 as a new deafness gene, which will impact future diagnosis and treatment for deaf patients.

Published
2021
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