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1. HostSeq: a Canadian whole genome sequencing and clinical data resource

Author: Yoo, S, Garg, E, Elliott, LT, Hung, RJ, Halevy, AR, Brooks, JD, Bull, SB, Gagnon, F, Greenwood, CMT, Lawless, JF, Paterson, AD, Sun, L, Zawati, MH, Lerner-Ellis, J, Abraham, RJS, Birol, I, Bourque, G, Garant, J-M, Gosselin, C, Li, J, Whitney, J, Thiruvahindrapuram, B, Herbrick, J-A, Lorenti, M, Reuter, MS, Adeoye, OO, Liu, S, Allen, U, Bernier, FP, Biggs, CM, Cheung, AM, Cowan, J, Herridge, M, Maslove, DM, Modi, BP, Mooser, V, Morris, SK, Ostrowski, M, Parekh, RS, Pfeffer, G, Suchowersky, O, Taher, J, Upton, J, Warren, RL, Yeung, RSM, Aziz, N, Turvey, SE, Knoppers, BM, Lathrop, M, Jones, SJM, Scherer, SW, and Strug, LJ
Published: 2023
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2. Predictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders.

Author: D'Abate, L, Walker, S, Yuen, RKC, Tammimies, K, Buchanan, JA, Davies, RW, Thiruvahindrapuram, B, Wei, J, Brian, J, Bryson, SE, Dobkins, K, Howe, J, Landa, R, Leef, J, Messinger, D, Ozonoff, S, Smith, IM, Stone, WL, Warren, ZE, Young, G, Zwaigenbaum, L, and Scherer, SW
Subjects: Humans, Genetic Predisposition to Disease, Risk Factors, Pedigree, Siblings, Genomics, Phenotype, Genome, Human, Child, Preschool, Family Health, Female, Male, DNA Copy Number Variations, Autism Spectrum Disorder, Child, Preschool, Genome, Human
Abstract: Identification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically.
Published: 2019

3. Corrigendum.

Author: Le Duc, D, Giulivi, C, Hiatt, SM, Napoli, E, Panoutsopoulos, A, De Crescenzo, AH, Kotzaeridou, U, Syrbe, S, Anagnostou, E, Azage, M, Bend, R, Begtrup, A, Brown, NJ, Büttner, B, Cho, MT, Cooper, GM, Doering, JH, Dubourg, C, Everman, DB, Hildebrand, MS, Santos, FJR, Kellam, B, Keller-Ramey, J, Lemke, JR, Liu, S, Niyazov, D, Payne, K, Person, R, Quélin, C, Schnur, RE, Smith, BT, Strober, J, Walker, S, Wallis, M, Walsh, L, Yang, S, Yuen, RKC, Ziegler, A, Sticht, H, Pride, MC, Orosco, L, Martínez-Cerdenõ, V, Silverman, JL, Crawley, JN, Scherer, SW, Zarbalis, KS, and Jamra, R
Subjects: Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract: In the original version of this article, authors Jill L. Silverman and Stephen W. Scherer were listed with incorrect affiliations; this has now been corrected.
Published: 2019

4. Predictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders

Author: D’Abate, L, Walker, S, Yuen, RKC, Tammimies, K, Buchanan, JA, Davies, RW, Thiruvahindrapuram, B, Wei, J, Brian, J, Bryson, SE, Dobkins, K, Howe, J, Landa, R, Leef, J, Messinger, D, Ozonoff, S, Smith, IM, Stone, WL, Warren, ZE, Young, G, Zwaigenbaum, L, and Scherer, SW
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Human Genome, Intellectual and Developmental Disabilities (IDD), Pediatric, Autism, Brain Disorders, Clinical Research, Mental Health, Genetic Testing, 2.1 Biological and endogenous factors, Aetiology, Mental health, Autism Spectrum Disorder, Child, Preschool, DNA Copy Number Variations, Family Health, Female, Genetic Predisposition to Disease, Genome, Human, Genomics, Humans, Male, Pedigree, Phenotype, Risk Factors, Siblings
Abstract: Identification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically.
Published: 2019

5. Psychiatric gene discoveries shape evidence on ADHD’s biology

Author: Thapar, A, Martin, J, Mick, E, Arias Vásquez, A, Langley, K, Scherer, SW, Schachar, R, Crosbie, J, Williams, N, Franke, B, Elia, J, Glessner, J, Hakonarson, H, Owen, MJ, Faraone, SV, O'Donovan, MC, and Holmans, P
Subjects: Biological Psychology, Biomedical and Clinical Sciences, Psychology, Pediatric, Neurosciences, Attention Deficit Hyperactivity Disorder (ADHD), Autism, Biotechnology, Genetics, Schizophrenia, Brain Disorders, Mental Health, Human Genome, Intellectual and Developmental Disabilities (IDD), 2.1 Biological and endogenous factors, Aetiology, Mental health, Good Health and Well Being, Adolescent, Attention Deficit Disorder with Hyperactivity, Autistic Disorder, Biological Psychiatry, Canada, Child, Child, Preschool, DNA Copy Number Variations, Databases, Nucleic Acid, Europe, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Ireland, Male, Neurodevelopmental Disorders, Polymorphism, Single Nucleotide, United Kingdom, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract: A strong motivation for undertaking psychiatric gene discovery studies is to provide novel insights into unknown biology. Although attention-deficit hyperactivity disorder (ADHD) is highly heritable, and large, rare copy number variants (CNVs) contribute to risk, little is known about its pathogenesis and it remains commonly misunderstood. We assembled and pooled five ADHD and control CNV data sets from the United Kingdom, Ireland, United States of America, Northern Europe and Canada. Our aim was to test for enrichment of neurodevelopmental gene sets, implicated by recent exome-sequencing studies of (a) schizophrenia and (b) autism as a means of testing the hypothesis that common pathogenic mechanisms underlie ADHD and these other neurodevelopmental disorders. We also undertook hypothesis-free testing of all biological pathways. We observed significant enrichment of individual genes previously found to harbour schizophrenia de novo non-synonymous single-nucleotide variants (SNVs; P=5.4 × 10(-4)) and targets of the Fragile X mental retardation protein (P=0.0018). No enrichment was observed for activity-regulated cytoskeleton-associated protein (P=0.23) or N-methyl-D-aspartate receptor (P=0.74) post-synaptic signalling gene sets previously implicated in schizophrenia. Enrichment of ADHD CNV hits for genes impacted by autism de novo SNVs (P=0.019 for non-synonymous SNV genes) did not survive Bonferroni correction. Hypothesis-free testing yielded several highly significantly enriched biological pathways, including ion channel pathways. Enrichment findings were robust to multiple testing corrections and to sensitivity analyses that excluded the most significant sample. The findings reveal that CNVs in ADHD converge on biologically meaningful gene clusters, including ones now established as conferring risk of other neurodevelopmental disorders.
Published: 2016

6. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy

Author: Mack, SC, Witt, H, Piro, RM, Gu, L, Zuyderduyn, S, Stütz, AM, Wang, X, Gallo, M, Garzia, L, Zayne, K, Zhang, X, Ramaswamy, V, Jäger, N, Jones, DTW, Sill, M, Pugh, TJ, Ryzhova, M, Wani, KM, Shih, DJH, Head, R, Remke, M, Bailey, SD, Zichner, T, Faria, CC, Barszczyk, M, Stark, S, Seker-Cin, H, Hutter, S, Johann, P, Bender, S, Hovestadt, V, Tzaridis, T, Dubuc, AM, Northcott, PA, Peacock, J, Bertrand, KC, Agnihotri, S, Cavalli, FMG, Clarke, I, Nethery-Brokx, K, Creasy, CL, Verma, SK, Koster, J, Wu, X, Yao, Y, Milde, T, Sin-Chan, P, Zuccaro, J, Lau, L, Pereira, S, Castelo-Branco, P, Hirst, M, Marra, MA, Roberts, SS, Fults, D, Massimi, L, Cho, YJ, Van Meter, T, Grajkowska, W, Lach, B, Kulozik, AE, von Deimling, A, Witt, O, Scherer, SW, Fan, X, Muraszko, KM, Kool, M, Pomeroy, SL, Gupta, N, Phillips, J, Huang, A, Tabori, U, Hawkins, C, Malkin, D, Kongkham, PN, Weiss, WA, Jabado, N, Rutka, JT, Bouffet, E, Korbel, JO, Lupien, M, Aldape, KD, Bader, GD, Eils, R, Lichter, P, Dirks, PB, Pfister, SM, Korshunov, A, and Taylor, MD
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Pediatric, Human Genome, Rare Diseases, Animals, Brain Neoplasms, CpG Islands, DNA Methylation, Embryonic Stem Cells, Ependymoma, Epigenesis, Genetic, Epigenomics, Female, Gene Expression Regulation, Neoplastic, Gene Silencing, Histones, Humans, Infant, Mice, Mice, Inbred NOD, Mice, SCID, Mutation, Phenotype, Polycomb Repressive Complex 2, Prognosis, Rhombencephalon, Xenograft Model Antitumor Assays, General Science & Technology
Abstract: Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.
Published: 2014

7. Additional file 1 of HostSeq: a Canadian whole genome sequencing and clinical data resource

Author: Yoo, S, Garg, E, Elliott, LT, Hung, RJ, Halevy, AR, Brooks, JD, Bull, SB, Gagnon, F, Greenwood, CMT, Lawless, JF, Paterson, AD, Sun, L, Zawati, MH, Lerner-Ellis, J, Abraham, RJS, Birol, I, Bourque, G, Garant, J-M, Gosselin, C, Li, J, Whitney, J, Thiruvahindrapuram, B, Herbrick, J-A, Lorenti, M, Reuter, MS, Adeoye, OO, Liu, S, Allen, U, Bernier, FP, Biggs, CM, Cheung, AM, Cowan, J, Herridge, M, Maslove, DM, Modi, BP, Mooser, V, Morris, SK, Ostrowski, M, Parekh, RS, Pfeffer, G, Suchowersky, O, Taher, J, Upton, J, Warren, RL, Yeung, RSM, Aziz, N, Turvey, SE, Knoppers, BM, Lathrop, M, Jones, SJM, Scherer, SW, and Strug, LJ
Abstract: Additional file 1: Table S1. HostSeq Core Consent Elements. In order to deposit datasets in HostSeq COVID-19 controlled-access Databank, all the elements in this table must be obtained in the research consent. Table S2. HostSeq Case Report Form. Table S3. Software used for processing WGS data. Table S4. List of HostSeq participating studies as described in respective protocols. Table S5. Distribution of sex and age across HostSeq studies (n = 9,427). SD: Standard deviation; IQR: interquartile range. Figure S1. Quality of HostSeq genomes. (A) Missing rate < 5%, (B) Contamination rate < 3%, (C) Mean coverage >10. Figure S2. Predicted population admixture and ancestry classification in HostSeq genomes. Each bar represents a genome. Proportion of African, East Asian and European ancestries is determined, and genomes classified into 8 ancestry groups using GRAF-pop. They are further categorized into 5 superpopulations: AFR - African and African-American, AMR - Latin American Asian and Latin American African, EAS - Asian-Pacific Islander and East Asian, SAS - South Asian, and EUR - European. 3% of genomes remain uncategorized. Figure S3. Genetic distances score of HostSeq genomes. The four genetic distances (GD1-4) scores from GRAF-pop represent the distance of each genome from several reference populations and are used to predict ancestry. Barycentric coordinates of GD1 and GD2 are used to predict admixture proportion of African, East Asian and European ancestries.
Published: 2023
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8. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author: Mullins, N, Kang, J, Campos, A, Coleman, JR, Edwards, AC, Galfalvy, H, Levey, DF, Lori, A, Shabalin, A, Starnawska, A, Su, M-H, Watson, HJ, Adams, M, Awasthi, S, Ganda, M, Hafferty, JD, Hishimoto, A, Kim, M, Okazaki, S, Otsuka, I, Ripke, S, Ware, EB, Bergen, AW, Berrettini, WH, Bohus, M, Brandt, H, Chang, X, Chen, WJ, Chen, H-C, Crawford, S, Crow, S, DiBlasi, E, Duriez, P, Fernandez-Aranda, F, Fichter, MM, Gallinger, S, Glatt, SJ, Gorwood, P, Guo, Y, Hakonarson, H, Halmi, KA, Hwu, H-G, Jain, S, Jamain, S, Jimenez-Murcia, S, Johnson, C, Kaplan, AS, Kaye, WH, Keel, PK, Kennedy, JL, Klump, KL, Li, D, Liao, S-C, Lieb, K, Lilenfeld, L, Liu, C-M, Magistretti, PJ, Marshall, CR, Mitchell, JE, Monson, ET, Myers, RM, Pinto, D, Powers, A, Ramoz, N, Roepke, S, Rozanov, V, Scherer, SW, Schmahl, C, Sokolowski, M, Strober, M, Thornton, LM, Treasure, J, Tsuang, MT, Witt, SH, Woodside, DB, Yilmaz, Z, Zillich, L, Adolfsson, R, Agartz, I, Air, TM, Alda, M, Alfredsson, L, Andreassen, OA, Anjorin, A, Appadurai, V, Artigas, MS, Van der Auwera, S, Azevedo, MH, Bass, N, Bau, CHD, Baune, BT, Bellivier, F, Berger, K, Biernacka, JM, Bigdeli, TB, Binder, EB, Boehnke, M, Boks, MP, Bosch, R, Braff, DL, Bryant, R, Budde, M, Byrne, EM, Cahn, W, Casas, M, Castelao, E, Cervilla, JA, Chaumette, B, Cichon, S, Corvin, A, Craddock, N, Craig, D, Degenhardt, F, Djurovic, S, Edenberg, HJ, Fanous, AH, Foo, JC, Forstner, AJ, Frye, M, Fullerton, JM, Gatt, JM, Gejman, P, Giegling, I, Grabe, HJ, Green, MJ, Grevet, EH, Grigoroiu-Serbanescu, M, Gutierrez, B, Guzman-Parra, J, Hamilton, SP, Hamshere, ML, Hartmann, A, Hauser, J, Heilmann-Heimbach, S, Hoffmann, P, Ising, M, Jones, I, Jones, LA, Jonsson, L, Kahn, RS, Kelsoe, JR, Kendler, KS, Kloiber, S, Koenen, KC, Kogevinas, M, Konte, B, Krebs, M-O, Lander, M, Lawrence, J, Leboyer, M, Lee, PH, Levinson, DF, Liao, C, Lissowska, J, Lucae, S, Mayoral, F, McElroy, SL, McGrath, P, McGuffin, P, McQuillin, A, Medland, SE, Mehta, D, Melle, I, Milaneschi, Y, Mitchell, PB, Molina, E, Morken, G, Mortensen, PB, Mueller-Myhsok, B, Nievergelt, C, Nimgaonkar, V, Noethen, MM, O'Donovan, MC, Ophoff, RA, Owen, MJ, Pato, C, Pato, MT, Penninx, BWJH, Pimm, J, Pistis, G, Potash, JB, Power, RA, Preisig, M, Quested, D, Ramos-Quiroga, JA, Reif, A, Ribases, M, Richarte, V, Rietschel, M, Rivera, M, Roberts, A, Roberts, G, Rouleau, GA, Rovaris, DL, Rujescu, D, Sanchez-Mora, C, Sanders, AR, Schofield, PR, Schulze, TG, Scott, LJ, Serretti, A, Shi, J, Shyn, S, Sirignano, L, Sklar, P, Smeland, OB, Smoller, JW, Sonuga-Barke, EJS, Spalletta, G, Strauss, JS, Swiatkowska, B, Trzaskowski, M, Turecki, G, Vilar-Ribo, L, Vincent, JB, Voelzke, H, Walters, JTR, Weickert, CS, Weickert, TW, Weissman, MM, Williams, LM, Wray, NR, Zai, CC, Ashley-Koch, AE, Beckham, JC, Hauser, ER, Hauser, MA, Kimbrel, NA, Lindquist, JH, McMahon, B, Oslin, DW, Qin, X, Agerbo, E, Borglum, AD, Breen, G, Erlangsen, A, Esko, T, Gelernter, J, Hougaard, DM, Kessler, RC, Kranzler, HR, Li, QS, Martin, NG, McIntosh, AM, Mors, O, Nordentoft, M, Olsen, CM, Porteous, D, Ursano, RJ, Wasserman, D, Werge, T, Whiteman, DC, Bulik, CM, Coon, H, Demontis, D, Docherty, AR, Kuo, P-H, Lewis, CM, Mann, JJ, Renteria, ME, Smith, DJ, Stahl, EA, Stein, MB, Streit, F, Willour, V, Ruderfer, DM, Mullins, N, Kang, J, Campos, A, Coleman, JR, Edwards, AC, Galfalvy, H, Levey, DF, Lori, A, Shabalin, A, Starnawska, A, Su, M-H, Watson, HJ, Adams, M, Awasthi, S, Ganda, M, Hafferty, JD, Hishimoto, A, Kim, M, Okazaki, S, Otsuka, I, Ripke, S, Ware, EB, Bergen, AW, Berrettini, WH, Bohus, M, Brandt, H, Chang, X, Chen, WJ, Chen, H-C, Crawford, S, Crow, S, DiBlasi, E, Duriez, P, Fernandez-Aranda, F, Fichter, MM, Gallinger, S, Glatt, SJ, Gorwood, P, Guo, Y, Hakonarson, H, Halmi, KA, Hwu, H-G, Jain, S, Jamain, S, Jimenez-Murcia, S, Johnson, C, Kaplan, AS, Kaye, WH, Keel, PK, Kennedy, JL, Klump, KL, Li, D, Liao, S-C, Lieb, K, Lilenfeld, L, Liu, C-M, Magistretti, PJ, Marshall, CR, Mitchell, JE, Monson, ET, Myers, RM, Pinto, D, Powers, A, Ramoz, N, Roepke, S, Rozanov, V, Scherer, SW, Schmahl, C, Sokolowski, M, Strober, M, Thornton, LM, Treasure, J, Tsuang, MT, Witt, SH, Woodside, DB, Yilmaz, Z, Zillich, L, Adolfsson, R, Agartz, I, Air, TM, Alda, M, Alfredsson, L, Andreassen, OA, Anjorin, A, Appadurai, V, Artigas, MS, Van der Auwera, S, Azevedo, MH, Bass, N, Bau, CHD, Baune, BT, Bellivier, F, Berger, K, Biernacka, JM, Bigdeli, TB, Binder, EB, Boehnke, M, Boks, MP, Bosch, R, Braff, DL, Bryant, R, Budde, M, Byrne, EM, Cahn, W, Casas, M, Castelao, E, Cervilla, JA, Chaumette, B, Cichon, S, Corvin, A, Craddock, N, Craig, D, Degenhardt, F, Djurovic, S, Edenberg, HJ, Fanous, AH, Foo, JC, Forstner, AJ, Frye, M, Fullerton, JM, Gatt, JM, Gejman, P, Giegling, I, Grabe, HJ, Green, MJ, Grevet, EH, Grigoroiu-Serbanescu, M, Gutierrez, B, Guzman-Parra, J, Hamilton, SP, Hamshere, ML, Hartmann, A, Hauser, J, Heilmann-Heimbach, S, Hoffmann, P, Ising, M, Jones, I, Jones, LA, Jonsson, L, Kahn, RS, Kelsoe, JR, Kendler, KS, Kloiber, S, Koenen, KC, Kogevinas, M, Konte, B, Krebs, M-O, Lander, M, Lawrence, J, Leboyer, M, Lee, PH, Levinson, DF, Liao, C, Lissowska, J, Lucae, S, Mayoral, F, McElroy, SL, McGrath, P, McGuffin, P, McQuillin, A, Medland, SE, Mehta, D, Melle, I, Milaneschi, Y, Mitchell, PB, Molina, E, Morken, G, Mortensen, PB, Mueller-Myhsok, B, Nievergelt, C, Nimgaonkar, V, Noethen, MM, O'Donovan, MC, Ophoff, RA, Owen, MJ, Pato, C, Pato, MT, Penninx, BWJH, Pimm, J, Pistis, G, Potash, JB, Power, RA, Preisig, M, Quested, D, Ramos-Quiroga, JA, Reif, A, Ribases, M, Richarte, V, Rietschel, M, Rivera, M, Roberts, A, Roberts, G, Rouleau, GA, Rovaris, DL, Rujescu, D, Sanchez-Mora, C, Sanders, AR, Schofield, PR, Schulze, TG, Scott, LJ, Serretti, A, Shi, J, Shyn, S, Sirignano, L, Sklar, P, Smeland, OB, Smoller, JW, Sonuga-Barke, EJS, Spalletta, G, Strauss, JS, Swiatkowska, B, Trzaskowski, M, Turecki, G, Vilar-Ribo, L, Vincent, JB, Voelzke, H, Walters, JTR, Weickert, CS, Weickert, TW, Weissman, MM, Williams, LM, Wray, NR, Zai, CC, Ashley-Koch, AE, Beckham, JC, Hauser, ER, Hauser, MA, Kimbrel, NA, Lindquist, JH, McMahon, B, Oslin, DW, Qin, X, Agerbo, E, Borglum, AD, Breen, G, Erlangsen, A, Esko, T, Gelernter, J, Hougaard, DM, Kessler, RC, Kranzler, HR, Li, QS, Martin, NG, McIntosh, AM, Mors, O, Nordentoft, M, Olsen, CM, Porteous, D, Ursano, RJ, Wasserman, D, Werge, T, Whiteman, DC, Bulik, CM, Coon, H, Demontis, D, Docherty, AR, Kuo, P-H, Lewis, CM, Mann, JJ, Renteria, ME, Smith, DJ, Stahl, EA, Stein, MB, Streit, F, Willour, V, and Ruderfer, DM
Abstract: BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
Published: 2022

9. Rare copy number variation in posttraumatic stress disorder.

Author: Maihofer, AX, Engchuan, W, Huguet, G, Klein, M, MacDonald, JR, Shanta, O, Thiruvahindrapuram, B, Jean-Louis, M, Saci, Z, Jacquemont, S, Scherer, SW, Ketema, E, Aiello, AE, Amstadter, AB, Avdibegović, E, Babic, D, Baker, DG, Bisson, JI, Boks, MP, Bolger, EA, Bryant, RA, Bustamante, AC, Caldas-de-Almeida, JM, Cardoso, G, Deckert, J, Delahanty, DL, Domschke, K, Dunlop, BW, Dzubur-Kulenovic, A, Evans, A, Feeny, NC, Franz, CE, Gautam, A, Geuze, E, Goci, A, Hammamieh, R, Jakovljevic, M, Jett, M, Jones, I, Kaufman, ML, Kessler, RC, King, AP, Kremen, WS, Lawford, BR, Lebois, LAM, Lewis, C, Liberzon, I, Linnstaedt, SD, Lugonja, B, Luykx, JJ, Lyons, MJ, Mavissakalian, MR, McLaughlin, KA, McLean, SA, Mehta, D, Mellor, R, Morris, CP, Muhie, S, Orcutt, HK, Peverill, M, Ratanatharathorn, A, Risbrough, VB, Rizzo, A, Roberts, AL, Rothbaum, AO, Rothbaum, BO, Roy-Byrne, P, Ruggiero, KJ, Rutten, BPF, Schijven, D, Seng, JS, Sheerin, CM, Sorenson, MA, Teicher, MH, Uddin, M, Ursano, RJ, Vinkers, CH, Voisey, J, Weber, H, Winternitz, S, Xavier, M, Yang, R, McD Young, R, Zoellner, LA, Psychiatric Genomics Consortium PTSD Working Group, Psychiatric Genomics Consortium CNV Working Group, Salem, RM, Shaffer, RA, Wu, T, Ressler, KJ, Stein, MB, Koenen, KC, Sebat, J, Nievergelt, CM, Maihofer, AX, Engchuan, W, Huguet, G, Klein, M, MacDonald, JR, Shanta, O, Thiruvahindrapuram, B, Jean-Louis, M, Saci, Z, Jacquemont, S, Scherer, SW, Ketema, E, Aiello, AE, Amstadter, AB, Avdibegović, E, Babic, D, Baker, DG, Bisson, JI, Boks, MP, Bolger, EA, Bryant, RA, Bustamante, AC, Caldas-de-Almeida, JM, Cardoso, G, Deckert, J, Delahanty, DL, Domschke, K, Dunlop, BW, Dzubur-Kulenovic, A, Evans, A, Feeny, NC, Franz, CE, Gautam, A, Geuze, E, Goci, A, Hammamieh, R, Jakovljevic, M, Jett, M, Jones, I, Kaufman, ML, Kessler, RC, King, AP, Kremen, WS, Lawford, BR, Lebois, LAM, Lewis, C, Liberzon, I, Linnstaedt, SD, Lugonja, B, Luykx, JJ, Lyons, MJ, Mavissakalian, MR, McLaughlin, KA, McLean, SA, Mehta, D, Mellor, R, Morris, CP, Muhie, S, Orcutt, HK, Peverill, M, Ratanatharathorn, A, Risbrough, VB, Rizzo, A, Roberts, AL, Rothbaum, AO, Rothbaum, BO, Roy-Byrne, P, Ruggiero, KJ, Rutten, BPF, Schijven, D, Seng, JS, Sheerin, CM, Sorenson, MA, Teicher, MH, Uddin, M, Ursano, RJ, Vinkers, CH, Voisey, J, Weber, H, Winternitz, S, Xavier, M, Yang, R, McD Young, R, Zoellner, LA, Psychiatric Genomics Consortium PTSD Working Group, Psychiatric Genomics Consortium CNV Working Group, Salem, RM, Shaffer, RA, Wu, T, Ressler, KJ, Stein, MB, Koenen, KC, Sebat, J, and Nievergelt, CM
Abstract: Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10-8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further.
Published: 2022

10. HostSeq : A Canadian Whole Genome Sequencing and Clinical Data Resource

Author: Yoo, S, primary, Garg, E, additional, Elliott, LT, additional, Hung, RJ, additional, Halevy, AR, additional, Brooks, JD, additional, Bull, SB, additional, Gagnon, F, additional, Greenwood, CMT, additional, Lawless, JF, additional, Paterson, AD, additional, Sun, L, additional, Zawati, MH, additional, Lerner-Ellis, J, additional, Abraham, RJS, additional, Birol, I, additional, Bourque, G, additional, Garant, J-M, additional, Gosselin, C, additional, Li, J, additional, Whitney, J, additional, Thiruvahindrapuram, B, additional, Herbrick, J-A, additional, Lorenti, M, additional, Reuter, MS, additional, Adeoye, NO, additional, Liu, S, additional, Allen, U, additional, Bernier, FP, additional, Biggs, CM, additional, Cheung, AM, additional, Cowan, J, additional, Herridge, M, additional, Maslove, DM, additional, Modi, BP, additional, Mooser, V, additional, Morris, SK, additional, Ostrowski, M, additional, Parekh, RS, additional, Pfeffer, G, additional, Suchowersky, O, additional, Taher, J, additional, Upton, J, additional, Warren, RL, additional, Yeung, RSM, additional, Aziz, N, additional, Turvey, SE, additional, Knoppers, BM, additional, Lathrop, M, additional, Jones, SJM, additional, Scherer, SW, additional, and Strug, LJ, additional
Published: 2022
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11. Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies

Author: Munn-Chernoff, MA, Johnson, EC, Chou, YL, Coleman, JRI, Thornton, LM, Walters, RK, Yilmaz, Z, Baker, JH, Hübel, C, Gordon, S, Medland, SE, Watson, HJ, Gaspar, HA, Bryois, J, Hinney, A, Leppä, VM, Mattheisen, M, Ripke, S, Yao, S, Giusti-Rodríguez, P, Hanscombe, KB, Adan, RAH, Alfredsson, L, Ando, T, Andreassen, OA, Berrettini, WH, Boehm, I, Boni, C, Boraska Perica, V, Buehren, K, Burghardt, R, Cassina, M, Cichon, S, Clementi, M, Cone, RD, Courtet, P, Crow, S, Crowley, JJ, Danner, UN, Davis, OS, Zwaan, M, Dedoussis, G, Degortes, D, DeSocio, JE, Dick, DM, Dikeos, D, Dina, C, Dmitrzak-Weglarz, M, Docampo, E, Duncan, LE, Egberts, K, Ehrlich, S, Escaramís, G, Esko, T, Estivill, X, Farmer, A, Favaro, A, Fernández-Aranda, F, Fichter, MM, Fischer, K, Föcker, M, Foretova, L, Forstner, AJ, Forzan, M, Franklin, CS, Gallinger, S, Giegling, I, Giuranna, J, Gonidakis, F, Gorwood, P, Gratacos Mayora, M, Guillaume, S, Guo, Y, Hakonarson, H, Hatzikotoulas, K, Hauser, J, Hebebrand, J, Helder, SG, Herms, S, Herpertz-Dahlmann, B, Herzog, W, Huckins, LM, Hudson, JI, Imgart, H, Inoko, H, Janout, V, Jiménez-Murcia, S, Julià, A, Kalsi, G, Kaminská, D, Karhunen, L, Karwautz, A, Kas, MJH, Kennedy, JL, Keski-Rahkonen, A, Kiezebrink, K, Kim, YR, Klump, KL, Knudsen, GP, La Via, MC, Le Hellard, S, Levitan, RD, Li, D, Lilenfeld, L, Lin, BD, Lissowska, J, Luykx, J, Magistretti, PJ, Maj, M, Mannik, K, Marsal, S, Marshall, CR, Mattingsdal, M, McDevitt, S, McGuffin, P, Metspalu, A, Meulenbelt, I, Micali, N, Mitchell, K, Monteleone, A M, Monteleone, P, Nacmias, B, Navratilova, M, Ntalla, I, O'Toole, JK, Ophoff, Roel, Padyukov, L, Palotie, A, Pantel, J, Papezova, H, Pinto, D, Rabionet, R, Raevuori, A, Ramoz, N, Reichborn-Kjennerud, T, Ricca, V, Ripatti, S, Ritschel, F, Roberts, M, Rotondo, A, Rujescu, D, Rybakowski, F, Santonastaso, P, Scherag, A, Scherer, SW, Schmidt, U, Schork, NJ, Schosser, A, Seitz, J, Slachtova, L, Slagboom, PE, Slof-Op't Landt, MCT, Slopien, A, Sorbi, S, ?wi?tkowska, B, Szatkiewicz, JP, Tachmazidou, I, Tenconi, E, Tortorella, A, Tozzi, F, Treasure, J, Tsitsika, A, Tyszkiewicz-Nwafor, M, Tziouvas, K, van Elburg, AA, van Furth, EF, Wagner, G, Walton, E, Widen, E, Zeggini, E, Zerwas, S, Zipfel, S, Bergen, AW, Boden, JM, Brandt, H, Crawford, S, Halmi, KA, Horwood, LJ, Johnson, C, Kaplan, AS, Kaye, WH, Mitchell, J E, Olsen, CM, Pearson, JF, Pedersen, NL, Strober, M, Werge, T, Whiteman, DC, Woodside, DB, Grove, J, Henders, AK, Larsen, J T, Parker, R, Petersen, LV, Jordan, J, Kennedy, MA, Birgegård, A, Lichtenstein, P, Norring, C, Landén, M, Mortensen, PB, Polimanti, R, McClintick, JN, Adkins, AE, Aliev, F, Bacanu, SA, Batzler, A, Bertelsen, S, Biernacka, JM, Bigdeli, TB, Chen, L S, Clarke, TK, Degenhardt, F, Docherty, AR, Edwards, AC, Foo, JC, Fox, L, Frank, J, Hack, LM, Hartmann, AM, Hartz, SM, Heilmann-Heimbach, S, Hodgkinson, C, Hoffmann, P, Hottenga, JJ, Konte, B, Lahti, J, Lahti-Pulkkinen, M, Lai, D, Ligthart, L, Loukola, A, Maher, BS, Mbarek, H, McIntosh, AM, McQueen, MB, Meyers, JL, Milaneschi, Y, Palviainen, T, Peterson, RE, Ryu, E, Saccone, N L, Salvatore, JE, Sanchez-Roige, S, Schwandt, M, Sherva, R, Streit, F, Strohmaier, J, Thomas, N, Wang, JCY, Webb, BT, Wedow, R, Wetherill, L, Wills, AG, Zhou, H, Boardman, JD, Chen, D, Choi, D S, Copeland, WE, Culverhouse, RC, Dahmen, N, Degenhardt, L, Domingue, BW, Frye, MA, Gäebel, W, Hayward, C, Ising, M, Keyes, M, Kiefer, F, Koller, G, Kramer, J (John), Kuperman, S, Lucae, S, Lynskey, MT, Maier, W, Mann, K, Männistö, S, Müller-Myhsok, B, Murray, AD, Nurnberger, JI, Preuss, U, Räikkönen, K, Reynolds, MD, Ridinger, M, Scherbaum, N, Schuckit, MA, Soyka, M, Treutlein, J, Witt, SH, Wodarz, N, Zill, P, Adkins, DE, Boomsma, DI, Bierut, LJ, Brown, S, Bucholz, KK, Costello, EJ, Wit, HJ, Diazgranados, N, Eriksson, JG, Farrer, LA, Foroud, TM, Gillespie, NA, Goate, AM, Goldman, D, Grucza, RA, Hancock, DB, Harris, KM, Hesselbrock, V, Hewitt, JK, Hopfer, CJ, Iacono, WG, Johnson, E O, Karpyak, VM, Kendler, KS, Kranzler, HR, Krauter, K, Lind, PA, McGue, M, MacKillop, J, Madden, PA, Maes, HH, Magnusson, PKE, Nelson, EC, Nöthen, MM, Palmer, AA, Penninx, BWJH, Porjesz, B, Rice, JP, Rietschel, M, Riley, BP, Rose, RJ, Shen, PH, Silberg, J, Stallings, MC, Tarter, RE, Vanyukov, MM, Vrieze, S, Wall, TL, Whitfield, JB, Zhao, H, Neale, BM, Wade, TD, Heath, AC, Montgomery, GW, Martin, NG, Sullivan, PF, Kaprio, J, Breen, G, Gelernter, J, Edenberg, HJ, Bulik, CM, Agrawal, A, Munn-Chernoff, MA, Johnson, EC, Chou, YL, Coleman, JRI, Thornton, LM, Walters, RK, Yilmaz, Z, Baker, JH, Hübel, C, Gordon, S, Medland, SE, Watson, HJ, Gaspar, HA, Bryois, J, Hinney, A, Leppä, VM, Mattheisen, M, Ripke, S, Yao, S, Giusti-Rodríguez, P, Hanscombe, KB, Adan, RAH, Alfredsson, L, Ando, T, Andreassen, OA, Berrettini, WH, Boehm, I, Boni, C, Boraska Perica, V, Buehren, K, Burghardt, R, Cassina, M, Cichon, S, Clementi, M, Cone, RD, Courtet, P, Crow, S, Crowley, JJ, Danner, UN, Davis, OS, Zwaan, M, Dedoussis, G, Degortes, D, DeSocio, JE, Dick, DM, Dikeos, D, Dina, C, Dmitrzak-Weglarz, M, Docampo, E, Duncan, LE, Egberts, K, Ehrlich, S, Escaramís, G, Esko, T, Estivill, X, Farmer, A, Favaro, A, Fernández-Aranda, F, Fichter, MM, Fischer, K, Föcker, M, Foretova, L, Forstner, AJ, Forzan, M, Franklin, CS, Gallinger, S, Giegling, I, Giuranna, J, Gonidakis, F, Gorwood, P, Gratacos Mayora, M, Guillaume, S, Guo, Y, Hakonarson, H, Hatzikotoulas, K, Hauser, J, Hebebrand, J, Helder, SG, Herms, S, Herpertz-Dahlmann, B, Herzog, W, Huckins, LM, Hudson, JI, Imgart, H, Inoko, H, Janout, V, Jiménez-Murcia, S, Julià, A, Kalsi, G, Kaminská, D, Karhunen, L, Karwautz, A, Kas, MJH, Kennedy, JL, Keski-Rahkonen, A, Kiezebrink, K, Kim, YR, Klump, KL, Knudsen, GP, La Via, MC, Le Hellard, S, Levitan, RD, Li, D, Lilenfeld, L, Lin, BD, Lissowska, J, Luykx, J, Magistretti, PJ, Maj, M, Mannik, K, Marsal, S, Marshall, CR, Mattingsdal, M, McDevitt, S, McGuffin, P, Metspalu, A, Meulenbelt, I, Micali, N, Mitchell, K, Monteleone, A M, Monteleone, P, Nacmias, B, Navratilova, M, Ntalla, I, O'Toole, JK, Ophoff, Roel, Padyukov, L, Palotie, A, Pantel, J, Papezova, H, Pinto, D, Rabionet, R, Raevuori, A, Ramoz, N, Reichborn-Kjennerud, T, Ricca, V, Ripatti, S, Ritschel, F, Roberts, M, Rotondo, A, Rujescu, D, Rybakowski, F, Santonastaso, P, Scherag, A, Scherer, SW, Schmidt, U, Schork, NJ, Schosser, A, Seitz, J, Slachtova, L, Slagboom, PE, Slof-Op't Landt, MCT, Slopien, A, Sorbi, S, ?wi?tkowska, B, Szatkiewicz, JP, Tachmazidou, I, Tenconi, E, Tortorella, A, Tozzi, F, Treasure, J, Tsitsika, A, Tyszkiewicz-Nwafor, M, Tziouvas, K, van Elburg, AA, van Furth, EF, Wagner, G, Walton, E, Widen, E, Zeggini, E, Zerwas, S, Zipfel, S, Bergen, AW, Boden, JM, Brandt, H, Crawford, S, Halmi, KA, Horwood, LJ, Johnson, C, Kaplan, AS, Kaye, WH, Mitchell, J E, Olsen, CM, Pearson, JF, Pedersen, NL, Strober, M, Werge, T, Whiteman, DC, Woodside, DB, Grove, J, Henders, AK, Larsen, J T, Parker, R, Petersen, LV, Jordan, J, Kennedy, MA, Birgegård, A, Lichtenstein, P, Norring, C, Landén, M, Mortensen, PB, Polimanti, R, McClintick, JN, Adkins, AE, Aliev, F, Bacanu, SA, Batzler, A, Bertelsen, S, Biernacka, JM, Bigdeli, TB, Chen, L S, Clarke, TK, Degenhardt, F, Docherty, AR, Edwards, AC, Foo, JC, Fox, L, Frank, J, Hack, LM, Hartmann, AM, Hartz, SM, Heilmann-Heimbach, S, Hodgkinson, C, Hoffmann, P, Hottenga, JJ, Konte, B, Lahti, J, Lahti-Pulkkinen, M, Lai, D, Ligthart, L, Loukola, A, Maher, BS, Mbarek, H, McIntosh, AM, McQueen, MB, Meyers, JL, Milaneschi, Y, Palviainen, T, Peterson, RE, Ryu, E, Saccone, N L, Salvatore, JE, Sanchez-Roige, S, Schwandt, M, Sherva, R, Streit, F, Strohmaier, J, Thomas, N, Wang, JCY, Webb, BT, Wedow, R, Wetherill, L, Wills, AG, Zhou, H, Boardman, JD, Chen, D, Choi, D S, Copeland, WE, Culverhouse, RC, Dahmen, N, Degenhardt, L, Domingue, BW, Frye, MA, Gäebel, W, Hayward, C, Ising, M, Keyes, M, Kiefer, F, Koller, G, Kramer, J (John), Kuperman, S, Lucae, S, Lynskey, MT, Maier, W, Mann, K, Männistö, S, Müller-Myhsok, B, Murray, AD, Nurnberger, JI, Preuss, U, Räikkönen, K, Reynolds, MD, Ridinger, M, Scherbaum, N, Schuckit, MA, Soyka, M, Treutlein, J, Witt, SH, Wodarz, N, Zill, P, Adkins, DE, Boomsma, DI, Bierut, LJ, Brown, S, Bucholz, KK, Costello, EJ, Wit, HJ, Diazgranados, N, Eriksson, JG, Farrer, LA, Foroud, TM, Gillespie, NA, Goate, AM, Goldman, D, Grucza, RA, Hancock, DB, Harris, KM, Hesselbrock, V, Hewitt, JK, Hopfer, CJ, Iacono, WG, Johnson, E O, Karpyak, VM, Kendler, KS, Kranzler, HR, Krauter, K, Lind, PA, McGue, M, MacKillop, J, Madden, PA, Maes, HH, Magnusson, PKE, Nelson, EC, Nöthen, MM, Palmer, AA, Penninx, BWJH, Porjesz, B, Rice, JP, Rietschel, M, Riley, BP, Rose, RJ, Shen, PH, Silberg, J, Stallings, MC, Tarter, RE, Vanyukov, MM, Vrieze, S, Wall, TL, Whitfield, JB, Zhao, H, Neale, BM, Wade, TD, Heath, AC, Montgomery, GW, Martin, NG, Sullivan, PF, Kaprio, J, Breen, G, Gelernter, J, Edenberg, HJ, Bulik, CM, and Agrawal, A
Abstract: Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = −0.19 to −0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotyp
Published: 2021

12. Loss-of-function variants in CAPRIN1 in patients affected by autism spectrum disorder, language delay and intellectual disability with variable expressivity and incomplete penetrance

Author: Pavinato, L, Howe, Jl, Carli, D, Agolini, E, Coviello, Da, Van de Laar, Imbh, Pyb, Au, Di Gregorio, E, Giorgio, E, Pozzi, E, Ferrero, M, Cardaropoli, S, Delle Vedove, A, Salpietro, V, Zara, F, Novelli, A, Wirth, B, Ferrero, Gb, Scherer, Sw, and Brusco, A
Published: 2020

13. ExpansionHunter Denovo: a computational method for locating known and novel repeat expansions in short-read sequencing data

Author: Dolzhenko, E, Bennett, MF, Richmond, PA, Trost, B, Chen, S, van Vugt, JJFA, Nguyen, C, Narzisi, G, Gainullin, VG, Gross, AM, Lajoie, BR, Taft, RJ, Wasserman, WW, Scherer, SW, Veldink, JH, Bentley, DR, Yuen, RKC, Bahlo, M, Eberle, MA, Dolzhenko, E, Bennett, MF, Richmond, PA, Trost, B, Chen, S, van Vugt, JJFA, Nguyen, C, Narzisi, G, Gainullin, VG, Gross, AM, Lajoie, BR, Taft, RJ, Wasserman, WW, Scherer, SW, Veldink, JH, Bentley, DR, Yuen, RKC, Bahlo, M, and Eberle, MA
Abstract: Repeat expansions are responsible for over 40 monogenic disorders, and undoubtedly more pathogenic repeat expansions remain to be discovered. Existing methods for detecting repeat expansions in short-read sequencing data require predefined repeat catalogs. Recent discoveries emphasize the need for methods that do not require pre-specified candidate repeats. To address this need, we introduce ExpansionHunter Denovo, an efficient catalog-free method for genome-wide repeat expansion detection. Analysis of real and simulated data shows that our method can identify large expansions of 41 out of 44 pathogenic repeats, including nine recently reported non-reference repeat expansions not discoverable via existing methods.
Published: 2020

14. DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes

Author: Choufani, S, Gibson, WT, Turinsky, AL, Chung, BHY, Wang, T, Garg, K, Vitriolo, A, Cohen, ASA, Cyrus, S, Goodman, S, Chater-Diehl, E, Brzezinski, J, Brudno, M, Ming, LH, White, SM, Lynch, SA, Clericuzio, C, Temple, IK, Flinter, F, McConnell, V, Cushing, T, Bird, LM, Splitt, M, Kerr, B, Scherer, SW, Machado, J, Imagawa, E, Okamoto, N, Matsumoto, N, Testa, G, Iascone, M, Tenconi, R, Caluseriu, O, Mendoza-Londono, R, Chitayat, D, Cytrynbaum, C, Tatton-Brown, K, Weksberg, R, Choufani, S, Gibson, WT, Turinsky, AL, Chung, BHY, Wang, T, Garg, K, Vitriolo, A, Cohen, ASA, Cyrus, S, Goodman, S, Chater-Diehl, E, Brzezinski, J, Brudno, M, Ming, LH, White, SM, Lynch, SA, Clericuzio, C, Temple, IK, Flinter, F, McConnell, V, Cushing, T, Bird, LM, Splitt, M, Kerr, B, Scherer, SW, Machado, J, Imagawa, E, Okamoto, N, Matsumoto, N, Testa, G, Iascone, M, Tenconi, R, Caluseriu, O, Mendoza-Londono, R, Chitayat, D, Cytrynbaum, C, Tatton-Brown, K, and Weksberg, R
Abstract: Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID. The discovery of a functionally relevant signature with utility for diagnostic classification of sequence variants in EZH2, EED, and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research.
Published: 2020

15. Hemizygous deletions on chromosome 1p21.3 involving the DPYD gene in individuals with autism spectrum disorder

Author: Carter, MT, Nikkel, SM, Fernandez, BA, Marshall, CR, Noor, A, Lionel, AC, Prasad, A, Pinto, D, Joseph-George, AM, Noakes, C, Fairbrother-Davies, C, Roberts, W, Vincent, J, Weksberg, R, and Scherer, SW
Published: 2011
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16. Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa

Author: Watson HJ, Yilmaz Z, Thornton LM, Hübel C, Coleman JRI, Gaspar HA, Bryois J, Hinney A, Leppä VM, Mattheisen M, Medland SE, Ripke S, Yao S, Giusti-Rodríguez P, Anorexia Nervosa Genetics Initiative, Hanscombe KB, Purves KL, Eating Disorders Working Group of the Psychiatric Genomics Consortium, Adan RAH, Alfredsson L, Ando T, Andreassen OA, Baker JH, Berrettini WH, Boehm I, Boni C, Perica VB, Buehren K, Burghardt R, Cassina M, Cichon S, Clementi M, Cone RD, Courtet P, Crow S, Crowley JJ, Danner UN, Davis OSP, de Zwaan M, Dedoussis G, Degortes D, DeSocio JE, Dick DM, Dikeos D, Dina C, Dmitrzak-Weglarz M, Docampo E, Duncan LE, Egberts K, Ehrlich S, Escaramís G, Esko T, Estivill X, Farmer A, Favaro A, Fernández-Aranda F, Fichter MM, Fischer K, Föcker M, Foretova L, Forstner AJ, Forzan M, Franklin CS, Gallinger S, Giegling I, Giuranna J, Gonidakis F, Gorwood P, Mayora MG, Guillaume S, Guo Y, Hakonarson H, Hatzikotoulas K, Hauser J, Hebebrand J, Helder SG, Herms S, Herpertz-Dahlmann B, Herzog W, Huckins LM, Hudson JI, Imgart H, Inoko H, Janout V, Jiménez-Murcia S, Julià A, Kalsi G, Kaminská D, Kaprio J, Karhunen L, Karwautz A, Kas MJH, Kennedy JL, Keski-Rahkonen A, Kiezebrink K, Kim YR, Klareskog L, Klump KL, Knudsen GPS, La Via MC, Le Hellard S, Levitan RD, Li D, Lilenfeld L, Lin BD, Lissowska J, Luykx J, Magistretti PJ, Maj M, Mannik K, Marsal S, Marshall CR, Mattingsdal M, McDevitt S, McGuffin P, Metspalu A, Meulenbelt I, Micali N, Mitchell K, Monteleone AM, Monteleone P, Munn-Chernoff MA, Nacmias B, Navratilova M, Ntalla I, O'Toole JK, Ophoff RA, Padyukov L, Palotie A, Pantel J, Papezova H, Pinto D, Raquel Rabionet Janssen, Raevuori A, Ramoz N, Reichborn-Kjennerud T, Ricca V, Ripatti S, Ritschel F, Roberts M, Rotondo A, Rujescu D, Rybakowski F, Santonastaso P, Scherag A, Scherer SW, Schmidt U, Schork NJ, Schosser A, Seitz J, Slachtova L, Slagboom PE, Slof-Op 't Landt MCT, Slopien A, Sorbi S, Swiatkowska B, Szatkiewicz JP, Tachmazidou I, Tenconi E, Tortorella A, Tozzi F, Treasure J, Tsitsika A, Tyszkiewicz-Nwafor M, Tziouvas K, van Elburg AA, van Furth EF, Wagner G, Walton E, Widen E, Zeggini E, Zerwas S, Zipfel S, Bergen AW, Boden JM, Brandt H, Crawford S, Halmi KA, Horwood LJ, Johnson C, Kaplan AS, Kaye WH, Mitchell JE, Olsen CM, Pearson JF, Pedersen NL, Strober M, Werge T, Whiteman DC, Woodside DB, Stuber GD, Gordon S, Grove J, Henders AK, Juréus A, Kirk KM, Larsen JT, Parker R, Petersen L, Jordan J, Kennedy M, Montgomery GW, Wade TD, Birgegård A, Lichtenstein P, Norring C, Landén M, Martin NG, Mortensen PB, Sullivan PF, Breen G, and Bulik CM
Subjects: mental disorders
Abstract: Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness 1 , affecting 0.9-4% of women and 0.3% of men 2-4 , with twin-based heritability estimates of 50-60% 5 . Mortality rates are higher than those in other psychiatric disorders 6 , and outcomes are unacceptably poor 7 . Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI) 8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.
Published: 2019

17. Genetic mapping of a new Lafora progressive myoclonus epilepsy locus (EPM2B) on 6p22

Author: Chan, EM, Bulman, DE, Paterson, AD, Turnbull, J, Andermann, E, Andermann, F, Rouleau, GA, Delgado-Escueta, AV, Scherer, SW, and Minassian, BA
Subjects: Medical genetics -- Research -- Analysis, Chromosome mapping -- Analysis -- Research -- Genetic aspects, Epilepsy -- Research -- Genetic aspects, Health
Abstract: Background: Lafora disease is a progressive myoclonus epilepsy with polyglucosan accumulations and a peculiar neurodegeneration with generalised organellar disintegration. It causes severe seizures, leading to dementia and eventually death in [...]
Published: 2003

18. Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes

Author: Loviglio MN, Leleu M, Männik K, Passeggeri M, Giannuzzi G, van der Werf I, Waszak SM, Zazhytska M, Roberts-Caldeira I, Gheldof N, Migliavacca E, Alfaiz AA, Hippolyte L, Maillard AM, 2p15 Consortium, 16p112 Consortium, Merla G, Van Dijck A, Kooy RF, Sanlaville D, Rosenfeld JA, Shaffer LG, Andrieux J, Marshall C, Scherer SW, Shen Y, Gusella JF, Thorsteinsdottir U, Thorleifsson G, Dermitzakis ET, Deplancke B, Beckmann JS, Rougemont J, Jacquemont S, Reymond A, Loviglio, Mn, Leleu, M, Männik, K, Passeggeri, M, Giannuzzi, G, van der Werf, I, Waszak, Sm, Zazhytska, M, Roberts-Caldeira, I, Gheldof, N, Migliavacca, E, Alfaiz, Aa, Hippolyte, L, Maillard, Am, 2p15, Consortium, 16p112, Consortium, Merla, G, Van Dijck, A, Kooy, Rf, Sanlaville, D, Rosenfeld, Ja, Shaffer, Lg, Andrieux, J, Marshall, C, Scherer, Sw, Shen, Y, Gusella, Jf, Thorsteinsdottir, U, Thorleifsson, G, Dermitzakis, Et, Deplancke, B, Beckmann, J, Rougemont, J, Jacquemont, S, and Reymond, A
Abstract: Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts' maps could uncover functionally and clinically related genes.
Published: 2017

19. Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia

Author: Anney, RJL, Ripke, S, Anttila, V, Grove, J, Holmans, P, Huang, H, Klei, L, Lee, PH, Medland, SE, Neale, B, Robinson, E, Weiss, LA, Zwaigenbaum, L, Yu, TW, Wittemeyer, K, Willsey, AJ, Wijsman, EM, Werge, T, Wassink, TH, Waltes, R, Walsh, CA, Wallace, S, Vorstman, JAS, Vieland, VJ, Vicente, AM, Vanengeland, H, Tsang, K, Thompson, AP, Szatmari, P, Svantesson, O, Steinberg, S, Stefansson, K, Stefansson, H, State, MW, Soorya, L, Silagadze, T, Scherer, SW, Schellenberg, GD, Sandin, S, Sanders, SJ, Saemundsen, E, Rouleau, GA, Rogé, B, Roeder, K, Roberts, W, Reichert, J, Reichenberg, A, Rehnström, K, Regan, R, Poustka, F, Poultney, CS, Piven, J, Pinto, D, Pericak-Vance, MA, Pejovic-Milovancevic, M, Pedersen, MG, Pedersen, CB, Paterson, AD, and Parr, JR
Subjects: mental disorders
Abstract: © 2017 The Author(s). Background: Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR)
Published: 2017

20. Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications

Author: Ombrello MJ, Arthur VL, Remmers EF, Hinks A, Tachmazidou I, Grom AA, Foell D, Martini A, Gattorno M, Özen S, Prahalad S, Zeft AS, Bohnsack JF, Ilowite NT, Mellins ED, Russo R, Len C, Hilario MO, Oliveira S, Yeung RS, Rosenberg AM, Wedderburn LR, Anton-Lopez J, Haas JP, Rosen-Wolff A, Minden K, Tenbrock K, Demirkaya E, Cobb J, Baskin E, Signa S, Shuldiner E, Duerr RH, Achkar JP, Kamboh MI, Kaufman KM, Kottyan LC, Pinto D, Scherer SW, Alarcón-Riquelme ME, Docampo E, Estivill X, Gül A, British Society of Pediatric and Adolescent Rheumatology (BSPAR) Study Group, In, Langefeld CD, Thompson S, Zeggini E, Kastner DL, Woo P, and Thomson W
Subjects: musculoskeletal diseases, genetic structures, Gene Polymorphism, Juvenile Idiopathic Arthritis, Adult Onset Still's Disease
Abstract: OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of conditions unified by the presence of chronic childhood arthritis without an identifiable cause. Systemic JIA (sJIA) is a rare form of JIA characterised by systemic inflammation. sJIA is distinguished from other forms of JIA by unique clinical features and treatment responses that are similar to autoinflammatory diseases. However, approximately half of children with sJIA develop destructive, long-standing arthritis that appears similar to other forms of JIA. Using genomic approaches, we sought to gain novel insights into the pathophysiology of sJIA and its relationship with other forms of JIA. METHODS: We performed a genome-wide association study of 770 children with sJIA collected in nine countries by the International Childhood Arthritis Genetics Consortium. Single nucleotide polymorphisms were tested for association with sJIA. Weighted genetic risk scores were used to compare the genetic architecture of sJIA with other JIA subtypes. RESULTS: The major histocompatibility complex locus and a locus on chromosome 1 each showed association with sJIA exceeding the threshold for genome-wide significance, while 23 other novel loci were suggestive of association with sJIA. Using a combination of genetic and statistical approaches, we found no evidence of shared genetic architecture between sJIA and other common JIA subtypes. CONCLUSIONS: The lack of shared genetic risk factors between sJIA and other JIA subtypes supports the hypothesis that sJIA is a unique disease process and argues for a different classification framework. Research to improve sJIA therapy should target its unique genetics and specific pathophysiological pathways.
Published: 2017

21. Molecular analysis of the PDS gene in Pendred syndrome

Author: Coyle, B, Reardon, W, Herbrick, JA, Tsui, LC, Gausden, E, Lee, J, Coffey, R, Grueters, A, Grossman4, A, Phelps, PD, Luxon, L, Kendall-Taylor, P, Scherer, SW, and Trembath, RC
Subjects: food and beverages
Abstract: Pendred syndrome is an autosomal recessive disorder characterized by the association between sensorineural hearing loss and thyroid swelling or goitre and is likely to be the most common form of syndromic deafness. Within the thyroid gland of affected individuals, iodide is incompletely organified with variable effects upon thyroid hormone biosynthesis, whilst the molecular basis of the hearing loss is unknown. The PDS gene has been identified by positional cloning of chromosome 7q31, within the Pendred syndrome critical linkage interval and encodes for a putative ion transporter called pendrin. We have investigated a cohort of 56 kindreds, all with features suggestive of a diagnosis of Pendred syndrome. Molecular analysis of the PDS gene identified 47 of the 60 (78%) mutant alleles in 31 families (includes three homozygous consanguineous kindreds and one extended family segregating three mutant alleles). Moreover, four recurrent mutations accounted for 35 (74%) of PDS disease chromosomes detected and haplotype analysis would favour common founders rather than mutational hotspots within the PDS gene. Whilst these findings demonstrate molecular heterogeneity for PDS mutations associated with Pendred syndrome, this study would support the use of molecular analysis of the PDS gene in the assessment of families with congenital hearing loss.
Published: 2016

22. Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes

Author: Loviglio, M. N, Leleu, M., Männik, K., Passeggeri, M., Giannuzzi, G., van der Werf, I., Waszak, S. M., Zazhytska, M., Roberts Caldeira, I., Gheldof, N., Migliavacca, E., Alfaiz, A. A., Hippolyte, L., Maillard, A. M., van Dijck, A., Kooy, R. F., Sanlaville, D., Rosenfeld, J. A., Shaffer, L. G., Andrieux, J., Marshall, C., Scherer, S. W., Shen, Y., Gusella, J. F., Thorsteinsdottir, U., Thorleifsson, G., Dermitzakis, E. T., Deplancke, B., Beckmann, J. S., Rougemont, J., Jacquemont, S., Reymond, A., Collaborators: Loviglio MN, Männik, K, van der Werf, I, Giannuzzi, G, Zazhytska, M, Gheldof, N, Migliavacca, E, Alfaiz, Aa, Roberts Caldeira, I, Hippolyte, L, Maillard, Am, Ferrarini, A, Butschi, Fn, Conrad, B, Addor, Mc, Belfiore, M, Roetzer, K, Dijck, Av, Blaumeiser, B, Kooy, F, Roelens, F, Dheedene, A, Chiaie, Bd, Menten, B, Oostra, A, Caberg, Jh, Carter, M, Kellam, B, Stavropoulos, Dj, Marshall, C, Scherer, Sw, Weksberg, R, Cytrynbaum, C, Bassett, A, Lowther, C, Gillis, J, Mackay, S, Bache, I, Ousager, Lb, Smerdel, Mp, Graakjaer, J, Kjaergaard, S, Metspalu, A, Mathieu, M, Bonneau, D, Guichet, A, Parent, P, Férec, C, Gerard, M, Plessis, G, Lespinasse, J, Masurel, A, Marle, N, Faivre, L, Callier, P, Layet, V, Meur, Nl, Le Goff, C, Duban Bedu, B, Sukno, S, Boute, O, Andrieux, J, Blanchet, P, Geneviève, D, Puechberty, J, Schneider, A, Leheup, B, Jonveaux, P, Mercier, S, David, A, Le Caignec, C, de Pontual, L, Pipiras, E, Jacquette, A, Keren, B, Gilbert Dussardier, B, Bilan, F, Goldenberg, A, Chambon, P, Toutain, A, Till, M, Sanlaville, D, Leube, B, Royer Pokora, B, Grabe, Hj, Schmidt, Co, Schurmann, C, Homuth, G, Thorleifsson, G, Thorsteinsdottir, U, Bernardini, L, Novelli, A, Micale, L, Merla, G, Zollino, M, Mari, Francesca, Rizzo, Cl, Renieri, Alessandra, Silengo, M, Vulto van Silfhout AT, Schouten, M, Pfundt, R, de Leeuw, N, Vansenne, F, Maas, Sm, Barge Schaapveld DQ, Knegt, Ac, Stadheim, B, Rodningen, O, Houge, G, Price, S, Hawkes, L, Campbell, C, Kini, U, Vogt, J, Walters, R, Blakemore, A, Gusella, Jf, Shen, Y, Scott, D, Bacino, Ca, Tsuchiya, K, Ladda, R, Sell, S, Asamoah, A, Hamati, Ai, Rosenfeld, Ja, Shaffer, Lg, Mitchell, E, Hodge, Jc, Beckmann, Js, Jacquemont, S, Reymond, A, Ewans, Lj, Mowat, D, Walker, J, Amor, Dj, Esch, Hv, Leroy, P, Bamforth, Js, Babu, D, Isidor, B, Didonato, N, Hackmann, K, Passeggeri, M, Haeringen, Av, Smith, R, Ellingwood, S, Farber, Dm, Puri, V, Zadeh, N, Weaver, Dd, Miller, M, Wilks, T, Jorgez, Cj, Lafayette, D, Blaumeiser, Bettina, 2p15 Consortium, 16p11.2 Consortium, Loviglio, M.N., Männik, K., van der Werf, I., Giannuzzi, G., Zazhytska, M., Gheldof, N., Migliavacca, E., Alfaiz, A.A., Roberts-Caldeira, I., Hippolyte, L., Maillard, A.M., Ferrarini, A., Butschi, F.N., Conrad, B., Addor, M.C., Belfiore, M., Roetzer, K., Dijck, A.V., Blaumeiser, B., Kooy, F., Roelens, F., Dheedene, A., Chiaie, B.D., Menten, B., Oostra, A., Caberg, J.H., Carter, M., Kellam, B., Stavropoulos, D.J., Marshall, C., Scherer, S.W., Weksberg, R., Cytrynbaum, C., Bassett, A., Lowther, C., Gillis, J., MacKay, S., Bache, I., Ousager, L.B., Smerdel, M.P., Graakjaer, J., Kjaergaard, S., Metspalu, A., Mathieu, M., Bonneau, D., Guichet, A., Parent, P., Férec, C., Gerard, M., Plessis, G., Lespinasse, J., Masurel, A., Marle, N., Faivre, L., Callier, P., Layet, V., Meur, N.L., Le Goff, C., Duban-Bedu, B., Sukno, S., Boute, O., Andrieux, J., Blanchet, P., Geneviève, D., Puechberty, J., Schneider, A., Leheup, B., Jonveaux, P., Mercier, S., David, A., Le Caignec, C., de Pontual, L., Pipiras, E., Jacquette, A., Keren, B., Gilbert-Dussardier, B., Bilan, F., Goldenberg, A., Chambon, P., Toutain, A., Till, M., Sanlaville, D., Leube, B., Royer-Pokora, B., Grabe, H.J., Schmidt, C.O., Schurmann, C., Homuth, G., Thorleifsson, G., Thorsteinsdottir, U., Bernardini, L., Novelli, A., Micale, L., Merla, G., Zollino, M., Mari, F., Rizzo, C.L., Renieri, A., Silengo, M., Vulto-van Silfhout, A.T., Schouten, M., Pfundt, R., de Leeuw, N., Vansenne, F., Maas, S.M., Barge-Schaapveld, D.Q., Knegt, A.C., Stadheim, B., Rodningen, O., Houge, G., Price, S., Hawkes, L., Campbell, C., Kini, U., Vogt, J., Walters, R., Blakemore, A., Gusella, J.F., Shen, Y., Scott, D., Bacino, C.A., Tsuchiya, K., Ladda, R., Sell, S., Asamoah, A., Hamati, A.I., Rosenfeld, J.A., Shaffer, L.G., Mitchell, E., Hodge, J.C., Beckmann, J.S., Jacquemont, S., Reymond, A., Ewans, L.J., Mowat, D., Walker, J., Amor, D.J., Esch, H.V., Leroy, P., Bamforth, J.S., Babu, D., Isidor, B., DiDonato, N., Hackmann, K., Passeggeri, M., Haeringen, A.V., Smith, R., Ellingwood, S., Farber, D.M., Puri, V., Zadeh, N., Weaver, D.D., Miller, M., Wilks, T., Jorgez, C.J., Lafayette, D., Other departments, and Human Genetics
Subjects: 0301 basic medicine, Male, Microcephaly, Autism Spectrum Disorder, Obesity/genetics, Settore MED/03 - GENETICA MEDICA, Body Mass Index, Microcephaly/genetics, Gene duplication, Chromosome Duplication, ddc:576.5, Copy-number variation, Child, In Situ Hybridization, In Situ Hybridization, Fluorescence, Genetics, medicine.diagnostic_test, Chromosome Mapping, Middle Aged, Phenotype, Chromatin, Chemistry, Psychiatry and Mental Health, Child, Preschool, Female, Original Article, Chromosomes, Human, Pair 16/genetics, Megalencephaly/genetics, Chromosome Deletion, Autistic Disorder/genetics, Molecular Biology, Cellular and Molecular Neuroscience, Human, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, Adolescent, DNA Copy Number Variations, Locus (genetics), DNA Copy Number Variations/genetics, Biology, Aged, Autistic Disorder, Chromosomes, Human, Pair 16, Humans, Infant, Intellectual Disability, Megalencephaly, Obesity, Chromosomes, Fluorescence, Chromatin/metabolism, 03 medical and health sciences, medicine, Preschool, Gene, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Pair 16, medicine.disease, Intellectual Disability/genetics, Autism Spectrum Disorder/genetics, 030104 developmental biology, Human medicine, Chromosome Mapping/methods, Fluorescence in situ hybridization
Abstract: Contains fulltext : 174530.pdf (Publisher’s version ) (Open Access) Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts' maps could uncover functionally and clinically related genes.
Published: 2015

23. HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis

Author: Ombrello MJ, Remmers EF, Tachmazidou I, Grom A, Foell D, Haas JP, Martini A, Gattorno M, Özen S, Prahalad S, Zeft AS, Bohnsack JF, Mellins ED, Ilowite NT, Russo R, Len C, Hilario MO, Oliveira S, Yeung RS, Rosenberg A, Wedderburn LR, Anton-Lopez J, Schwarz T, Hinks A, Bilginer Y, Park J, Cobb J, Satorius CL, Han B, Baskin E, Signa S, Duerr RH, Achkar JP, Kamboh MI, Kaufman KM, Kottyan LC, Pinto D, Scherer SW, Alarcón-Riquelme ME, Docampo E, Estivill X, Gül A, British Society of Pediatric and Adolescent Rheumatology (BSPAR) Study Group, Childhood Arthritis Prospective Study (CAPS) Group, Randomized Placebo Phase Study of Rilonacept in sJIA (RAPPORT) Investigators, Sparks-Childhood Arthritis Response to Medication Study (CHARMS) Group, Biologically Based Outcome Predictors in JIA (BBOP) Group, de Bakker PI, Raychaudhuri S, Langefeld CD, Thompson S, Zeggini E, Thomson W, Kastner DL, Woo P, International Childhood Arthritis Genetics (INCHARGE) Consortium, and British Society of Pediatric and Adolescent Rheumatology BSPAR Study Group
Published: 2015

24. Cytogenetic prognostication within medulloblastoma subgroups

Author: Shih, DJH, Northcott, PA, Remke, M, Korshunov, A, Ramaswamy, V, Kool, M, Luu, B, Yao, Y, Wang, X, Dubuc, AM, Garzia, L, Peacock, J, Mack, SC, Wu, X, Rolider, A, Morrissy, AS, Cavalli, FMG, Jones, DTW, Zitterbart, K, Faria, CC, Schüller, U, Kren, L, Kumabe, T, Tominaga, T, Ra, YS, Garami, M, Hauser, P, Chan, JA, Robinson, S, Bognár, L, Klekner, A, Saad, AG, Liau, LM, Albrecht, S, Fontebasso, A, Cinalli, G, De Antonellis, P, Zollo, M, Cooper, MK, Thompson, RC, Bailey, S, Lindsey, JC, Di Rocco, C, Massimi, L, Michiels, EMC, Scherer, SW, Phillips, JJ, Gupta, N, Fan, X, Muraszko, KM, Vibhakar, R, Eberhart, CG, Fouladi, M, Lach, B, Jung, S, Wechsler-Reya, RJ, Fèvre-Montange, M, Jouvet, A, Jabado, N, Pollack, IF, Weiss, WA, Lee, JY, Cho, BK, Kim, SK, Wang, KC, Leonard, JR, Rubin, JB, De Torres, C, Lavarino, C, Mora, J, Cho, YJ, Tabori, U, Olson, JM, Gajjar, A, Packer, RJ, Rutkowski, S, Pomeroy, SL, French, PJ, Kloosterhof, NK, Kros, JM, Van Meir, EG, Clifford, SC, Bourdeaut, F, Delattre, O, Doz, FF, Hawkins, CE, Malkin, D, and Grajkowska, WA
Subjects: Male, Adolescent, Kruppel-Like Transcription Factors, Zinc Finger Protein Gli2, Risk Assessment, Proto-Oncogene Proteins c-myc, Cytogenetics, Young Adult, Risk Factors, Predictive Value of Tests, Biomarkers, Tumor, Humans, Hedgehog Proteins, Oncology & Carcinogenesis, Child, In Situ Hybridization, Fluorescence, Proportional Hazards Models, Chromosomes, Human, Pair 14, Oncology And Carcinogenesis, Chromosomes, Human, Pair 11, Gene Expression Profiling, Nuclear Proteins, Reproducibility of Results, Infant, Prognosis, Gene Expression Regulation, Neoplastic, Wnt Proteins, Tissue Array Analysis, Child, Preschool, Female, Medulloblastoma
Abstract: Purpose: Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. Patients and Methods: Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. Results: Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. Conclusion: Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials. © 2014 by American Society of Clinical Oncology.
Published: 2014

25. Recurrent duplications of the annexin A1 gene (ANXA1) in autism spectrum disorders

Author: Correia, CT, Conceição, IC, Oliveira, B, Coelho, J, Sousa, I, Sequeira, AF, Almeida, J, Café, C, Duque, F, Mouga, S, Roberts, W, Gao, K, Lowe, JK, Thiruvahindrapuram, B, Walker, S, Marshall, CR, Pinto, D, Geschwind, JI, Scherer, SW, Oliveira, G, and Vicente, AM
Subjects: Perturbação Autística, mental disorders, Anexina A1
Abstract: BACKGROUND: Validating the potential pathogenicity of copy number variants (CNVs) identified in genome-wide studies of autism spectrum disorders (ASD) requires detailed assessment of case/control frequencies, inheritance patterns, clinical correlations, and functional impact. Here, we characterize a small recurrent duplication in the annexin A1 (ANXA1) gene, identified by the Autism Genome Project (AGP) study. METHODS: From the AGP CNV genomic screen in 2,147 ASD individuals, we selected for characterization an ANXA1 gene duplication that was absent in 4,964 population-based controls. We further screened the duplication in a follow-up sample including 1,496 patients and 410 controls, and evaluated clinical correlations and family segregation. Sequencing of exonic/downstream ANXA1 regions was performed in 490 ASD patients for identification of additional variants. RESULTS: The ANXA1 duplication, overlapping the last four exons and 3'UTR region, had an overall prevalence of 11/3,643 (0.30%) in unrelated ASD patients but was not identified in 5,374 controls. Duplication carriers presented no distinctive clinical phenotype. Family analysis showed neuropsychiatric deficits and ASD traits in multiple relatives carrying the duplication, suggestive of a complex genetic inheritance. Sequencing of exonic regions and the 3'UTR identified 11 novel changes, but no obvious variants with clinical significance. CONCLUSIONS: We provide multilevel evidence for a role of ANXA1 in ASD etiology. Given its important role as mediator of glucocorticoid function in a wide variety of brain processes, including neuroprotection, apoptosis, and control of the neuroendocrine system, the results add ANXA1 to the growing list of rare candidate genetic etiological factors for ASD.
Published: 2014

26. Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3

Author: Williams, NM, Franke, B, Mick, E, Anney, RJL, Freitag, CM, Gill, M, Thapar, A, O'Donovan, MC, Owen, MJ, Holmans, P, Kent, L, Middleton, F, Zhang-James, Y, Liu, L, Meyer, J, Nguyen, TT, Romanos, J, Romanos, M, Seitz, C, Renner, TJ, Walitza, S, Warnke, A, Palmason, H, Buitelaar, J, Rommelse, N, Vasquez, AA, Hawi, Z, Langley, K, Sergeant, J, Steinhausen, HC, Roeyers, Herbert, Biederman, J, Zaharieva, I, Hakonarson, H, Elia, J, Lionel, AC, Crosbie, J, Marshall, CR, Schachar, R, Scherer, SW, Todorov, A, Smalley, SL, Loo, S, Nelson, S, Shtir, C, Asherson, P, Reif, A, Lesch, KP, Faraone, SV, Psychiatrie & Neuropsychologie, Farmacologie en Toxicologie, and RS: CARIM School for Cardiovascular Diseases
Subjects: CANDIDATE GENE, Canada, Adolescent, alpha7 Nicotinic Acetylcholine Receptor, Genetics and epigenetic pathways of disease [NCMLS 6], DCN MP - Plasticity and memory, Gene Dosage, Inheritance Patterns, Social Sciences, ASSOCIATION SCAN, DCN PAC - Perception action and control, Nicotinic, MICRODUPLICATIONS, Medical and Health Sciences, Mental health [NCEBP 9], Fluorescence, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], MOLECULAR-GENETICS, SCHIZOPHRENIA, Receptors, mental disorders, ADHD, Humans, Genetic Predisposition to Disease, DCN PAC - Perception action and control NCEBP 9 - Mental health, Polymorphism, Child, Preschool, QH426, CHROMOSOMAL DELETIONS, In Situ Hybridization, Psychiatry, AUTISM SPECTRUM DISORDER, Psychology and Cognitive Sciences, Single Nucleotide, Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3], R1, United States, United Kingdom, NICOTINIC RECEPTOR, Causality, Segmental Duplications, Attention Deficit Disorder with Hyperactivity, Genomic, RC0321, Female, DEFICIT/HYPERACTIVITY DISORDER, Genome-Wide Association Study
Abstract: Item does not contain fulltext OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology. METHOD: The authors performed a genome-wide analysis of large, rare CNVs (100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder. CONCLUSIONS: These findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5-3.6), this locus could be an important contributor to ADHD etiology. 01 februari 2012
Published: 2012

27. Synaptic, transcriptional and chromatin genes disrupted in autism.

Author: De Rubeis, S, He, X, Goldberg, AP, Poultney, CS, Samocha, K, Cicek, AE, Kou, Y, Liu, L, Fromer, M, Walker, S, Singh, T, Klei, L, Kosmicki, J, Shih-Chen, F, Aleksic, B, Biscaldi, M, Bolton, PF, Brownfeld, JM, Cai, J, Campbell, NG, Carracedo, A, Chahrour, MH, Chiocchetti, AG, Coon, H, Crawford, EL, Curran, SR, Dawson, G, Duketis, E, Fernandez, BA, Gallagher, L, Geller, E, Guter, SJ, Hill, RS, Ionita-Laza, J, Jimenz Gonzalez, P, Kilpinen, H, Klauck, SM, Kolevzon, A, Lee, I, Lei, I, Lei, J, Lehtimäki, T, Lin, C-F, Ma'ayan, A, Marshall, CR, McInnes, AL, Neale, B, Owen, MJ, Ozaki, N, Parellada, M, Parr, JR, Purcell, S, Puura, K, Rajagopalan, D, Rehnström, K, Reichenberg, A, Sabo, A, Sachse, M, Sanders, SJ, Schafer, C, Schulte-Rüther, M, Skuse, D, Stevens, C, Szatmari, P, Tammimies, K, Valladares, O, Voran, A, Li-San, W, Weiss, LA, Willsey, AJ, Yu, TW, Yuen, RKC, DDD Study, Homozygosity Mapping Collaborative for Autism, UK10K Consortium, Cook, EH, Freitag, CM, Gill, M, Hultman, CM, Lehner, T, Palotie, A, Schellenberg, GD, Sklar, P, State, MW, Sutcliffe, JS, Walsh, CA, Scherer, SW, Zwick, ME, Barett, JC, Cutler, DJ, Roeder, K, Devlin, B, Daly, MJ, Buxbaum, JD, De Rubeis, S, He, X, Goldberg, AP, Poultney, CS, Samocha, K, Cicek, AE, Kou, Y, Liu, L, Fromer, M, Walker, S, Singh, T, Klei, L, Kosmicki, J, Shih-Chen, F, Aleksic, B, Biscaldi, M, Bolton, PF, Brownfeld, JM, Cai, J, Campbell, NG, Carracedo, A, Chahrour, MH, Chiocchetti, AG, Coon, H, Crawford, EL, Curran, SR, Dawson, G, Duketis, E, Fernandez, BA, Gallagher, L, Geller, E, Guter, SJ, Hill, RS, Ionita-Laza, J, Jimenz Gonzalez, P, Kilpinen, H, Klauck, SM, Kolevzon, A, Lee, I, Lei, I, Lei, J, Lehtimäki, T, Lin, C-F, Ma'ayan, A, Marshall, CR, McInnes, AL, Neale, B, Owen, MJ, Ozaki, N, Parellada, M, Parr, JR, Purcell, S, Puura, K, Rajagopalan, D, Rehnström, K, Reichenberg, A, Sabo, A, Sachse, M, Sanders, SJ, Schafer, C, Schulte-Rüther, M, Skuse, D, Stevens, C, Szatmari, P, Tammimies, K, Valladares, O, Voran, A, Li-San, W, Weiss, LA, Willsey, AJ, Yu, TW, Yuen, RKC, DDD Study, Homozygosity Mapping Collaborative for Autism, UK10K Consortium, Cook, EH, Freitag, CM, Gill, M, Hultman, CM, Lehner, T, Palotie, A, Schellenberg, GD, Sklar, P, State, MW, Sutcliffe, JS, Walsh, CA, Scherer, SW, Zwick, ME, Barett, JC, Cutler, DJ, Roeder, K, Devlin, B, Daly, MJ, and Buxbaum, JD
Abstract: The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.
Published: 2014

28. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Author: Arking, D, Pulit, S, Crotti, L, van der Harst, P, Munroe, P, Koopmann, T, Sotoodehnia, N, Rossin, E, Morley, M, Wang, X, Johnson, A, Lundby, A, Gudbjartsson, D, Noseworthy, P, Eijgelsheim, M, Bradford, Y, Tarasov, K, Dörr, M, Müller-Nurasyid, M, Lahtinen, A, Nolte, I, Smith, A, Bis, J, Isaacs, A, Newhouse, S, Evans, D, Post, W, Waggott, D, Lyytikäinen, L, Hicks, A, Eisele, L, Ellinghaus, D, Hayward, C, Navarro, P, Ulivi, S, Tanaka, T, Tester, D, Chatel, S, Gustafsson, S, Kumari, M, Morris, R, Naluai, A, Padmanabhan, S, Kluttig, A, Strohmer, B, Panayiotou, A, Torres, M, Knoflach, M, Hubacek, J, Slowikowski, K, Raychaudhuri, S, Kumar, R, Harris, T, Launer, L, Shuldiner, A, Alonso, A, Bader, J, Ehret, G, Huang, H, Kao, W, Strait, J, Macfarlane, P, Brown, M, Caulfield, M, Samani, N, Kronenberg, F, Willeit, J, Smith, J, Greiser, K, Meyer Zu Schwabedissen, H, Werdan, K, Carella, M, Zelante, L, Heckbert, S, Psaty, B, Rotter, J, Kolcic, I, Polašek, O, Wright, A, Griffin, M, Daly, M, Arnar, D, Hólm, H, Thorsteinsdottir, U, Denny, J, Roden, D, Zuvich, R, Emilsson, V, Plump, A, Larson, M, O'Donnell, C, Yin, X, Bobbo, M, D'Adamo, A, Iorio, A, Sinagra, G, Carracedo, A, Cummings, S, Nalls, M, Jula, A, Kontula, K, Marjamaa, A, Oikarinen, L, Perola, M, Porthan, K, Erbel, R, Hoffmann, P, Jöckel, K, Kälsch, H, Nöthen, M, den Hoed, M, Loos, R, Thelle, D, Gieger, C, Meitinger, T, Perz, S, Peters, A, Prucha, H, Sinner, M, Waldenberger, M, de Boer, R, Franke, L, van der Vleuten, P, Beckmann, B, Martens, E, Bardai, A, Hofman, N, Wilde, A, Behr, E, Dalageorgou, C, Giudicessi, J, Medeiros-Domingo, A, Kyndt, F, Probst, V, Ghidoni, A, Insolia, R, Hamilton, R, Scherer, S, Brandimarto, J, Margulies, K, Moravec, C, Greco, M, Fuchsberger, C, O'Connell, J, Lee, W, Watt, G, Campbell, H, Wild, S, El Mokhtari, N, Frey, N, Asselbergs, F, Mateo Leach, I, Navis, G, van den Berg, M, van Veldhuisen, D, Kellis, M, Krijthe, B, Franco, O, Hofman, A, Kors, J, Uitterlinden, A, Witteman, J, Kedenko, L, Lamina, C, Oostra, B, Abecasis, G, Lakatta, E, Mulas, A, Orrú, M, Schlessinger, D, Uda, M, Markus, M, Völker, U, Snieder, H, Spector, T, Arnlöv, J, Lind, L, Sundström, J, Syvänen, A, Kivimaki, M, Kähönen, M, Mononen, N, Raitakari, O, Viikari, J, Adamkova, V, Kiechl, S, Brion, M, Nicolaides, A, Paulweber, B, Haerting, J, Dominiczak, A, Nyberg, F, Whincup, P, Hingorani, A, Schott, J, Bezzina, C, Ingelsson, E, Ferrucci, L, Gasparini, P, Wilson, J, Rudan, I, Franke, A, Mühleisen, T, Pramstaller, P, Lehtimäki, T, Paterson, A, Parsa, A, Liu, Y, van Duijn, C, Siscovick, D, Gudnason, V, Jamshidi, Y, Salomaa, V, Felix, S, Sanna, S, Ritchie, M, Stricker, B, Stefansson, K, Boyer, L, Cappola, T, Olsen, J, Lage, K, Schwartz, P, Kääb, S, Chakravarti, A, Ackerman, M, Pfeufer, A, de Bakker, P, Newton-Cheh, C, Arking, DE, Pulit, SL, Munroe, PB, Rossin, EJ, Johnson, AD, Gudbjartsson, DF, Noseworthy, PA, Tarasov, KV, Lahtinen, AM, Nolte, IM, Smith, AV, Bis, JC, Newhouse, SJ, Evans, DS, Post, WS, Lyytikäinen, LP, Hicks, AA, Tester, DJ, Morris, RW, Naluai, AT, Panayiotou, AG, Hubacek, JA, Kumar, RD, Harris, TB, Launer, LJ, Shuldiner, AR, Bader, JS, Kao, WH, Strait, JB, Macfarlane, PW, Caulfield, MJ, Samani, NJ, Smith, JG, Greiser, KH, Heckbert, SR, Psaty, BM, Rotter, JI, Wright, AF, Daly, MJ, Arnar, DO, Denny, JC, Roden, DM, Zuvich, RL, Plump, AS, Larson, MG, O'Donnell, CJ, D'Adamo, AP, Cummings, SR, Nalls, MA, Kontula, KK, Jöckel, KH, Nöthen, MM, Loos, RJ, Thelle, DS, Sinner, MF, de Boer, RA, van der Vleuten, PA, Beckmann, BM, Wilde, AA, Behr, ER, Giudicessi, JR, Hamilton, RM, Scherer, SW, Moravec, CE, Greco, MFD, O'Connell, JR, Lee, WK, Watt, GC, Wild, SH, El Mokhtari, NE, Asselbergs, FW, van den Berg, MP, van Veldhuisen, DJ, Krijthe, BP, Franco, OH, Kors, JA, Uitterlinden, AG, Witteman, JC, Oostra, BA, Abecasis, GR, Lakatta, EG, Markus, MR, Spector, TD, Syvänen, AC, Raitakari, OT, Viikari, JS, Nicolaides, AN, Dominiczak, AF, Whincup, PH, Hingorani, AD, Schott, JJ, Bezzina, CR, Wilson, JF, Mühleisen, TW, Pramstaller, PP, Lehtimäki, TJ, Paterson, AD, van Duijn, CM, Siscovick, DS, Felix, SB, Ritchie, MD, Stricker, BH, Boyer, LA, Cappola, TP, Olsen, JV, Schwartz, PJ, Ackerman, MJ, de Bakker, PI, Arking, D, Pulit, S, Crotti, L, van der Harst, P, Munroe, P, Koopmann, T, Sotoodehnia, N, Rossin, E, Morley, M, Wang, X, Johnson, A, Lundby, A, Gudbjartsson, D, Noseworthy, P, Eijgelsheim, M, Bradford, Y, Tarasov, K, Dörr, M, Müller-Nurasyid, M, Lahtinen, A, Nolte, I, Smith, A, Bis, J, Isaacs, A, Newhouse, S, Evans, D, Post, W, Waggott, D, Lyytikäinen, L, Hicks, A, Eisele, L, Ellinghaus, D, Hayward, C, Navarro, P, Ulivi, S, Tanaka, T, Tester, D, Chatel, S, Gustafsson, S, Kumari, M, Morris, R, Naluai, A, Padmanabhan, S, Kluttig, A, Strohmer, B, Panayiotou, A, Torres, M, Knoflach, M, Hubacek, J, Slowikowski, K, Raychaudhuri, S, Kumar, R, Harris, T, Launer, L, Shuldiner, A, Alonso, A, Bader, J, Ehret, G, Huang, H, Kao, W, Strait, J, Macfarlane, P, Brown, M, Caulfield, M, Samani, N, Kronenberg, F, Willeit, J, Smith, J, Greiser, K, Meyer Zu Schwabedissen, H, Werdan, K, Carella, M, Zelante, L, Heckbert, S, Psaty, B, Rotter, J, Kolcic, I, Polašek, O, Wright, A, Griffin, M, Daly, M, Arnar, D, Hólm, H, Thorsteinsdottir, U, Denny, J, Roden, D, Zuvich, R, Emilsson, V, Plump, A, Larson, M, O'Donnell, C, Yin, X, Bobbo, M, D'Adamo, A, Iorio, A, Sinagra, G, Carracedo, A, Cummings, S, Nalls, M, Jula, A, Kontula, K, Marjamaa, A, Oikarinen, L, Perola, M, Porthan, K, Erbel, R, Hoffmann, P, Jöckel, K, Kälsch, H, Nöthen, M, den Hoed, M, Loos, R, Thelle, D, Gieger, C, Meitinger, T, Perz, S, Peters, A, Prucha, H, Sinner, M, Waldenberger, M, de Boer, R, Franke, L, van der Vleuten, P, Beckmann, B, Martens, E, Bardai, A, Hofman, N, Wilde, A, Behr, E, Dalageorgou, C, Giudicessi, J, Medeiros-Domingo, A, Kyndt, F, Probst, V, Ghidoni, A, Insolia, R, Hamilton, R, Scherer, S, Brandimarto, J, Margulies, K, Moravec, C, Greco, M, Fuchsberger, C, O'Connell, J, Lee, W, Watt, G, Campbell, H, Wild, S, El Mokhtari, N, Frey, N, Asselbergs, F, Mateo Leach, I, Navis, G, van den Berg, M, van Veldhuisen, D, Kellis, M, Krijthe, B, Franco, O, Hofman, A, Kors, J, Uitterlinden, A, Witteman, J, Kedenko, L, Lamina, C, Oostra, B, Abecasis, G, Lakatta, E, Mulas, A, Orrú, M, Schlessinger, D, Uda, M, Markus, M, Völker, U, Snieder, H, Spector, T, Arnlöv, J, Lind, L, Sundström, J, Syvänen, A, Kivimaki, M, Kähönen, M, Mononen, N, Raitakari, O, Viikari, J, Adamkova, V, Kiechl, S, Brion, M, Nicolaides, A, Paulweber, B, Haerting, J, Dominiczak, A, Nyberg, F, Whincup, P, Hingorani, A, Schott, J, Bezzina, C, Ingelsson, E, Ferrucci, L, Gasparini, P, Wilson, J, Rudan, I, Franke, A, Mühleisen, T, Pramstaller, P, Lehtimäki, T, Paterson, A, Parsa, A, Liu, Y, van Duijn, C, Siscovick, D, Gudnason, V, Jamshidi, Y, Salomaa, V, Felix, S, Sanna, S, Ritchie, M, Stricker, B, Stefansson, K, Boyer, L, Cappola, T, Olsen, J, Lage, K, Schwartz, P, Kääb, S, Chakravarti, A, Ackerman, M, Pfeufer, A, de Bakker, P, Newton-Cheh, C, Arking, DE, Pulit, SL, Munroe, PB, Rossin, EJ, Johnson, AD, Gudbjartsson, DF, Noseworthy, PA, Tarasov, KV, Lahtinen, AM, Nolte, IM, Smith, AV, Bis, JC, Newhouse, SJ, Evans, DS, Post, WS, Lyytikäinen, LP, Hicks, AA, Tester, DJ, Morris, RW, Naluai, AT, Panayiotou, AG, Hubacek, JA, Kumar, RD, Harris, TB, Launer, LJ, Shuldiner, AR, Bader, JS, Kao, WH, Strait, JB, Macfarlane, PW, Caulfield, MJ, Samani, NJ, Smith, JG, Greiser, KH, Heckbert, SR, Psaty, BM, Rotter, JI, Wright, AF, Daly, MJ, Arnar, DO, Denny, JC, Roden, DM, Zuvich, RL, Plump, AS, Larson, MG, O'Donnell, CJ, D'Adamo, AP, Cummings, SR, Nalls, MA, Kontula, KK, Jöckel, KH, Nöthen, MM, Loos, RJ, Thelle, DS, Sinner, MF, de Boer, RA, van der Vleuten, PA, Beckmann, BM, Wilde, AA, Behr, ER, Giudicessi, JR, Hamilton, RM, Scherer, SW, Moravec, CE, Greco, MFD, O'Connell, JR, Lee, WK, Watt, GC, Wild, SH, El Mokhtari, NE, Asselbergs, FW, van den Berg, MP, van Veldhuisen, DJ, Krijthe, BP, Franco, OH, Kors, JA, Uitterlinden, AG, Witteman, JC, Oostra, BA, Abecasis, GR, Lakatta, EG, Markus, MR, Spector, TD, Syvänen, AC, Raitakari, OT, Viikari, JS, Nicolaides, AN, Dominiczak, AF, Whincup, PH, Hingorani, AD, Schott, JJ, Bezzina, CR, Wilson, JF, Mühleisen, TW, Pramstaller, PP, Lehtimäki, TJ, Paterson, AD, van Duijn, CM, Siscovick, DS, Felix, SB, Ritchie, MD, Stricker, BH, Boyer, LA, Cappola, TP, Olsen, JV, Schwartz, PJ, Ackerman, MJ, and de Bakker, PI
Abstract: The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD
Published: 2014

29. Mapping autism risk loci using genetic linkage and chromosomal rearrangements

Author: Szatmari, P, Paterson, AD, Zwaigenbaum, L, Roberts, W, Brian, J, Liu, XQ, Vincent, JB, Skaug, JL, Thompson, AP, Senman, L, Feuk, L, Qian, C, Bryson, SE, Jones, MB, Marshall, CR, Scherer, SW, Vieland, VJ, Bartlett, C, Mangin, LV, Goedken, R, Segre, A, Pericak-Vance, MA, Cuccaro, ML, Gilbert, JR, Wright, HH, Abramson, RK, Betancur, C, Bourgeron, T, Gillberg, C, Leboyer, M, Buxbaum, JD, Davis, KL, Hollander, E, Silverman, JM, Hallmayer, J, Lotspeich, L, Sutcliffe, JS, Haines, JL, Folstein, SE, Piven, J, Wassink, TH, Sheffield, V, Geschwind, DH, Bucan, M, Brown, WT, Cantor, RM, Constantino, JN, Gilliam, TC, Herbert, M, LaJonchere, C, Ledbetter, DH, Lese-Martin, C, Miller, J, Nelson, S, Samango-Sprouse, CA, Spence, S, State, M, Tanzi, RE, Coon, H, Dawson, G, Devlin, B, Estes, A, Flodman, P, Klei, L, McMahon, WM, Minshew, N, Munson, J, Korvatska, E, Rodier, PM, Schellenberg, GD, Smith, M, Spence, MA, Stodgell, C, Tepper, PG, Wijsman, EM, Yu, CE, Rogé, B, Mantoulan, C, Wittemeyer, K, Poustka, A, Felder, B, Klauck, SM, Schuster, C, Poustka, F, Bölte, S, Feineis-Matthews, S, Herbrecht, E, Schmötzer, G, Tsiantis, J, Papanikolaou, K, Maestrini, E, and Bacchelli, E
Subjects: mental disorders
Abstract: Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,168 families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs. © 2007 Nature Publishing Group.
Published: 2007

30. Involvement of the HLXB9 homeobox gene in Currarino syndrome [2]

Author: Torre, M, Jasonni, V, Seri, M, Martucciello, G, Verderio, D, Tsui, LC, Ponti, E, Belloni, E, Ferrari, M, and Scherer, SW
Subjects: Dna mutational analysis, Magnetic resonance imaging, Homeodomain proteins - genetics, Anal canal - abnormalities, Abnormalities, multiple - genetics - radiography
Abstract: published_or_final_version
Published: 2000

31. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Author: Craddock, N, Hurles, ME, Cardin, N, Pearson, RD, Plagnol, V, Robson, S, Vukcevic, D, Barnes, C, Conrad, DF, Giannoulatou, E, Holmes, C, Marchini, JL, Stirrups, K, Tobin, MD, Wain, LV, Yau, C, Aerts, J, Ahmad, T, Andrews, TD, Arbury, H, Attwood, A, Auton, A, Ball, SG, Balmforth, AJ, Barrett, JC, Barroso, I, Barton, A, Bennett, AJ, Bhaskar, S, Blaszczyk, K, Bowes, J, Brand, OJ, Braund, PS, Bredin, F, Breen, G, Brown, MJ, Bruce, IN, Bull, J, Burren, OS, Burton, J, Byrnes, J, Caesar, S, Clee, CM, Coffey, AJ, Connell, JMC, Cooper, JD, Dominiczak, AF, Downes, K, Drummond, HE, Dudakia, D, Dunham, A, Ebbs, B, Eccles, D, Edkins, S, Edwards, C, Elliot, A, Emery, P, Evans, DM, Evans, G, Eyre, S, Farmer, A, Ferrier, IN, Feuk, L, Fitzgerald, T, Flynn, E, Forbes, A, Forty, L, Franklyn, JA, Freathy, RM, Gibbs, P, Gilbert, P, Gokumen, O, Gordon-Smith, K, Gray, E, Green, E, Groves, CJ, Grozeva, D, Gwilliam, R, Hall, A, Hammond, N, Hardy, M, Harrison, P, Hassanali, N, Hebaishi, H, Hines, S, Hinks, A, Hitman, GA, Hocking, L, Howard, E, Howard, P, Howson, JMM, Hughes, D, Hunt, S, Isaacs, JD, Jain, M, Jewell, DP, Johnson, T, Jolley, JD, Jones, IR, Jones, LA, Kirov, G, Langford, CF, Lango-Allen, H, Lathrop, GM, Lee, J, Lee, KL, Lees, C, Lewis, K, Lindgren, CM, Maisuria-Armer, M, Maller, J, Mansfield, J, Martin, P, Massey, DCO, McArdle, WL, McGuffin, P, McLay, KE, Mentzer, A, Mimmack, ML, Morgan, AE, Morris, AP, Mowat, C, Myers, S, Newman, W, Nimmo, ER, O'Donovan, MC, Onipinla, A, Onyiah, I, Ovington, NR, Owen, MJ, Palin, K, Parnell, K, Pernet, D, Perry, JRB, Phillips, A, Pinto, D, Prescott, NJ, Prokopenko, I, Quail, MA, Rafelt, S, Rayner, NW, Redon, R, Reid, DM, Renwick, A, Ring, SM, Robertson, N, Russell, E, St Clair, D, Sambrook, JG, Sanderson, JD, Schuilenburg, H, Scott, CE, Scott, R, Seal, S, Shaw-Hawkins, S, Shields, BM, Simmonds, MJ, Smyth, DJ, Somaskantharajah, E, Spanova, K, Steer, S, Stephens, J, Stevens, HE, Stone, MA, Su, Z, Symmons, DPM, Thompson, JR, Thomson, W, Travers, ME, Turnbull, C, Valsesia, A, Walker, M, Walker, NM, Wallace, C, Warren-Perry, M, Watkins, NA, Webster, J, Weedon, MN, Wilson, AG, Woodburn, M, Wordsworth, BP, Young, AH, Zeggini, E, Carter, NP, Frayling, TM, Lee, C, McVean, G, Munroe, PB, Palotie, A, Sawcer, SJ, Scherer, SW, Strachan, DP, Tyler-Smith, C, Brown, MA, Burton, PR, Caulfield, MJ, Compston, A, Farrall, M, Gough, SCL, Hall, AS, Hattersley, AT, Hill, AVS, Mathew, CG, Pembrey, M, Satsangi, J, Stratton, MR, Worthington, J, Deloukas, P, Duncanson, A, Kwiatkowski, DP, McCarthy, MI, Ouwehand, WH, Parkes, M, Rahman, N, Todd, JA, Samani, NJ, Donnelly, P, Craddock, N, Hurles, ME, Cardin, N, Pearson, RD, Plagnol, V, Robson, S, Vukcevic, D, Barnes, C, Conrad, DF, Giannoulatou, E, Holmes, C, Marchini, JL, Stirrups, K, Tobin, MD, Wain, LV, Yau, C, Aerts, J, Ahmad, T, Andrews, TD, Arbury, H, Attwood, A, Auton, A, Ball, SG, Balmforth, AJ, Barrett, JC, Barroso, I, Barton, A, Bennett, AJ, Bhaskar, S, Blaszczyk, K, Bowes, J, Brand, OJ, Braund, PS, Bredin, F, Breen, G, Brown, MJ, Bruce, IN, Bull, J, Burren, OS, Burton, J, Byrnes, J, Caesar, S, Clee, CM, Coffey, AJ, Connell, JMC, Cooper, JD, Dominiczak, AF, Downes, K, Drummond, HE, Dudakia, D, Dunham, A, Ebbs, B, Eccles, D, Edkins, S, Edwards, C, Elliot, A, Emery, P, Evans, DM, Evans, G, Eyre, S, Farmer, A, Ferrier, IN, Feuk, L, Fitzgerald, T, Flynn, E, Forbes, A, Forty, L, Franklyn, JA, Freathy, RM, Gibbs, P, Gilbert, P, Gokumen, O, Gordon-Smith, K, Gray, E, Green, E, Groves, CJ, Grozeva, D, Gwilliam, R, Hall, A, Hammond, N, Hardy, M, Harrison, P, Hassanali, N, Hebaishi, H, Hines, S, Hinks, A, Hitman, GA, Hocking, L, Howard, E, Howard, P, Howson, JMM, Hughes, D, Hunt, S, Isaacs, JD, Jain, M, Jewell, DP, Johnson, T, Jolley, JD, Jones, IR, Jones, LA, Kirov, G, Langford, CF, Lango-Allen, H, Lathrop, GM, Lee, J, Lee, KL, Lees, C, Lewis, K, Lindgren, CM, Maisuria-Armer, M, Maller, J, Mansfield, J, Martin, P, Massey, DCO, McArdle, WL, McGuffin, P, McLay, KE, Mentzer, A, Mimmack, ML, Morgan, AE, Morris, AP, Mowat, C, Myers, S, Newman, W, Nimmo, ER, O'Donovan, MC, Onipinla, A, Onyiah, I, Ovington, NR, Owen, MJ, Palin, K, Parnell, K, Pernet, D, Perry, JRB, Phillips, A, Pinto, D, Prescott, NJ, Prokopenko, I, Quail, MA, Rafelt, S, Rayner, NW, Redon, R, Reid, DM, Renwick, A, Ring, SM, Robertson, N, Russell, E, St Clair, D, Sambrook, JG, Sanderson, JD, Schuilenburg, H, Scott, CE, Scott, R, Seal, S, Shaw-Hawkins, S, Shields, BM, Simmonds, MJ, Smyth, DJ, Somaskantharajah, E, Spanova, K, Steer, S, Stephens, J, Stevens, HE, Stone, MA, Su, Z, Symmons, DPM, Thompson, JR, Thomson, W, Travers, ME, Turnbull, C, Valsesia, A, Walker, M, Walker, NM, Wallace, C, Warren-Perry, M, Watkins, NA, Webster, J, Weedon, MN, Wilson, AG, Woodburn, M, Wordsworth, BP, Young, AH, Zeggini, E, Carter, NP, Frayling, TM, Lee, C, McVean, G, Munroe, PB, Palotie, A, Sawcer, SJ, Scherer, SW, Strachan, DP, Tyler-Smith, C, Brown, MA, Burton, PR, Caulfield, MJ, Compston, A, Farrall, M, Gough, SCL, Hall, AS, Hattersley, AT, Hill, AVS, Mathew, CG, Pembrey, M, Satsangi, J, Stratton, MR, Worthington, J, Deloukas, P, Duncanson, A, Kwiatkowski, DP, McCarthy, MI, Ouwehand, WH, Parkes, M, Rahman, N, Todd, JA, Samani, NJ, and Donnelly, P
Abstract: Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
Published: 2010

32. Autism spectrum disorder in the genetics clinic: a review

Author: Carter, MT, primary and Scherer, SW, additional
Published: 2013
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33. Hemizygous deletion of the syntaxin 1A gene in individuals with Williams syndrome: Letters to the editor

Author: Tsui, L-C, Osborne, LR, Soder, S, Shi, XM, Pober, B, Costa, T, and Scherer, SW
Subjects: Elastin - genetics, DNA-binding proteins - genetics, Gene deletion, Nerve tissue proteins - genetics, Antigens, surface - genetics
Abstract: published_or_final_version
Published: 1997

34. Characterization of the split hand split foot malformation locus SHFM1 at 7q21.3-q22.1 and analysis of a candidate gene for its expression during limb development

Author: Crackower, MA, Scherer, SW, Rommens, JM, Hui, CC, Poorkaj, P, Soder, S, Cobben, JM, Hudgins, L, Evans, JP, and Tsui, LC
Subjects: SEQUENCES, MOUSE
Abstract: Split hand/split foot malformation (SHFM) is a heterogeneous limb developmental disorder, characterized by missing digits and fusion of remaining digits. An autosomal dominant form of this disorder (SHFM1) has been mapped to 7q21.3-q22.1 on the basis of SHFM-associated chromosomal rearrangements, Utilizing a YAC contig across this region, we have defined a critical interval of 1.5 Mb by the analysis of six interstitial deletion patients and mapped the translocation breakpoints of seven ectrodactyly patients within the interval, To delineate the basic molecular defect underlying SHFM, we have searched for candidate genes in a 500 kb region containing five of the translocation breakpoints. Three genes were identified, two genes of the Distal-less (dll) homeobox gene family, DLX5 and DLX6 and a navel gene, which we named DSS1. DSS1 is predicted to encode a highly acidic polypeptide with no significant similarity to any known proteins but 100% amino acid sequence identity with its murine homolog (Dss1), Using RNA in situ hybridization analysis, we detected a tissue-specific expression profile for Dss1 in limb bud, craniofacial primordia and skin, A deficiency in expression of DSS1, DLX5 and/or DLX6 during development may explain the SHFM phenotypes.
Published: 1996

35. Heterogeneity of the autosomal dominant split hand/split foot malformation [6]

Author: Stephens, K, Evans, JP, Wijsman, EM, Kukolich, M, Scherer, SW, Tsui, LC, Palmer, S, and Zlotogora, J
Subjects: Genetic Heterogeneity, Foot Deformities, Congenital - classification - genetics, Chromosomes, Human, Pair 7, Hand Deformities, Congenital - classification - genetics, Genes, Dominant
Abstract: Reply to Zlotogora: Heterogeneity of the autosomal dominant split hand/split foot malformation, link_to_OA_fulltext
Published: 1995

36. MAPPING THE HUMAN GROWTH HORMONE-RELEASING HORMONE-RECEPTOR (GHRHR) GENE TO THE SHORT ARM OF CHROMOSOME-7 (7P13-P21) NEAR THE EPIDERMAL GROWTH-FACTOR RECEPTOR (EGFR) GENE

Author: VAMVAKOPOULOS, NC KUNZ, J OLBERDING, U SCHERER, SW and SIOUTOPOULOU, TO SCHNEIDER, V DURKIN, AS NIERMAN, WC
Published: 1994

37. Hemizygous deletions on chromosome 1p21.3 involving the DPYD gene in individuals with autism spectrum disorder

Author: Carter, MT, primary, Nikkel, SM, additional, Fernandez, BA, additional, Marshall, CR, additional, Noor, A, additional, Lionel, AC, additional, Prasad, A, additional, Pinto, D, additional, Joseph-George, AM, additional, Noakes, C, additional, Fairbrother-Davies, C, additional, Roberts, W, additional, Vincent, J, additional, Weksberg, R, additional, and Scherer, SW, additional
Published: 2010
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38. Mapping of three novel loci for non-syndromic autosomal recessive mental retardation (NS-ARMR) in consanguineous families from Pakistan

Author: Rafiq, MA, primary, Ansar, M, additional, Marshall, CR, additional, Noor, A, additional, Shaheen, N, additional, Mowjoodi, A, additional, Khan, MA, additional, Ali, G, additional, Amin-ud-Din, M, additional, Feuk, L, additional, Vincent, JB, additional, and Scherer, SW, additional
Published: 2010
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39. Holoprosencephaly and cleidocranial dysplasia in a patient due to two position‐effect mutations: case report and review of the literature

Author: Fernandez, BA, primary, Siegel‐Bartelt, J, additional, Herbrick, J‐AS, additional, Teshima, I, additional, and Scherer, SW, additional
Published: 2005
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40. Molecular definition of a narrow interval at 7q22.1 associated with myelodysplasia

Author: Johnson, EJ, primary, Scherer, SW, additional, Osborne, L, additional, Tsui, LC, additional, Oscier, D, additional, Mould, S, additional, and Cotter, FE, additional
Published: 1996
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41. Mitochondrial DNA haplogroups and mutations in children with acquired central demyelination.

Author: Venkateswaran S, Zheng K, Sacchetti M, Gagne D, Arnold DL, Sadovnick AD, Scherer SW, Banwell B, Bar-Or A, Simon DK, Canadian Pediatric Demyelinating Disease Network, Venkateswaran, S, Zheng, K, Sacchetti, M, Gagne, D, Arnold, D L, Sadovnick, A D, Scherer, S W, Banwell, B, and Bar-Or, A
Published: 2011
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42. Characterization of an autism-associated segmental maternal heterodisomy of the chromosome 15q11-13 region.

Author: Kwasnicka-Crawford DA, Roberts W, and Scherer SW
Abstract: Cytogenetic abnormalities in the Prader-Willi/Angelman syndrome (PWS/AS) critical region have been described in individuals with autism. Maternal duplications and linkage disequilibrium in families with autism suggest the existence of a susceptibility locus at 15q11-q13. Here, we describe a 6-year-old girl diagnosed with autism, developmental delay, and delayed expressive and receptive language. The karyotype was designated de novo 47, XX, idic(15)(q13). Fluorescence in situ hybridization (FISH) and molecular analysis with 15q11-q13 markers revealed an additional copy of the region being of maternal origin. Duplication of the 15q11-q13 segment represents the most consistent known chromosomal abnormality reported in association with autism. This present case report reinforces the hypothesis that additional copies of this chromosome segment are causally related to autism. [ABSTRACT FROM AUTHOR]
Published: 2007
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43. Progressive myoclonus epilepsy with polyglucosans (Lafora disease): evidence for a third locus.

Author: Chan EM, Omer S, Ahmed M, Bridges LR, Bennett C, Scherer SW, Minassian BA, Chan, E M, Omer, S, Ahmed, M, Bridges, L R, Bennett, C, Scherer, S W, and Minassian, B A
Published: 2004
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44. An inversion INV (4) (p12-p15.3) associated with autism implicates the 4p GABA receptor gene cluster

Author: Vincent, Jb, Choufani, S., Shin-ichi Horike, Skaug, J., Fernandez, B., and Scherer, Sw

45. Severe expressive-language delay related to duplication of the Williams-Beuren locus.

Author: Somerville MJ, Mervis CB, Young EJ, Seo E, del Campo M, Bamforth S, Peregrine E, Loo W, Lilley M, Pérez-Jurado LA, Morris CA, Scherer SW, Osborne LR, Somerville, Martin J, Mervis, Carolyn B, Young, Edwin J, Seo, Eul-Ju, del Campo, Miguel, Bamforth, Stephen, and Peregrine, Ella
Abstract: The Williams-Beuren syndrome (WBS) locus, at 7q11.23, is prone to recurrent chromosomal rearrangements, including the microdeletion that causes WBS, a multisystem condition with characteristic cardiovascular, cognitive, and behavioral features. It is hypothesized that reciprocal duplications of the WBS interval should also occur, and here we present such a case description. The most striking phenotype was a severe delay in expressive speech, in contrast to the normal articulation and fluent expressive language observed in persons with WBS. Our results suggest that specific genes at 7q11.23 are exquisitely sensitive to dosage alterations that can influence human language and visuospatial capabilities. [ABSTRACT FROM AUTHOR]
Published: 2005

46. Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders

Author: Joana Almeida, Christian R. Marshall, Hakon Hakonarson, Bárbara Oliveira, Anthony J. Griswold, Jacob A. S. Vorstman, Bhooma Thiruvahindrapuram, Suma Jacob, Judith Conroy, Alistair T. Pagnamenta, Christelle Cabrol, Jeremy R. Parr, Daniel H. Geschwind, Nancy J. Minshew, Xiao Xu, Richard Anney, Sven Bölte, Zhuozhi Wang, Emily L. Crawford, Elsa Delaby, Margaret A. Pericak-Vance, Joachim Hallmayer, Jonathan L. Haines, Dalila Pinto, Susana Mouga, Alexander Kolevzon, Elena Bacchelli, Frederico Duque, Bernie Devlin, Latha Soorya, Cátia Café, Kirsty Wing, Jennifer K. Lowe, Ana Tryfon, Stephen J. Guter, Geraldine Dawson, Tiago R. Magalhaes, Anthony J. Bailey, Michael Gill, Peter Szatmari, Steven Gallinger, Marion Pilorge, James S. Sutcliffe, Bridget A. Fernandez, Herman van Engeland, Catalina Betancur, Guiomar Oliveira, Andrew Green, Eftichia Duketis, Bernadette Rogé, Ann Le Couteur, Evdokia Anagnostou, Michelle Cotterchio, Daniele Merico, Giovanna Pellecchia, Jonathan Green, Regina Regan, Jillian P. Casey, Guiqing Cai, Gerard D. Schellenberg, Jennifer L. Howe, Elena Maestrini, Andrew D. Paterson, L. Alison McInnes, Patrick Bolton, Edwin H. Cook, Richard Delorme, Lambertus Klei, Thomas Bourgeron, Gillian Baird, Christine M. Freitag, Beth A. Dombroski, Andreas G. Chiocchetti, Sabine M. Klauck, Susan E. Folstein, Mafalda Barbosa, Anthony P. Monaco, Marion Leboyer, Nadia Bolshakova, Fritz Poustka, Richard Holt, Kerstin Wittemeyer, Wendy Roberts, Lonnie Zwaigenbaum, Louise Gallagher, Susan G. McGrew, Joseph D. Buxbaum, Graham Casey, Simon Wallace, Catherine Lord, Sean Brennan, Robert Ziman, Alison K. Merikangas, John I. Nurnberger, Christopher Gillberg, Ellen M. Wijsman, Astrid M. Vicente, Inȇs C. Conceição, Sean Ennis, Patricia Jiménez González, Hilary Coon, Raphael Bernier, John R. Gilbert, Ann P. Thompson, Susanne Thomson, Agatino Battaglia, Maretha de Jonge, Michael L. Cuccaro, Catarina Correia, Veronica J. Vieland, Stephen W. Scherer, Pauline Chaste, Departments of Psychiatry, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Seaver Autism Center-, The Mindich Child Health & Development Institute, Department of Psychiatry, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Seaver Autism Center for Research and Treatment, Friedman Brain Institute, The Mindich Child Health and Development Institute, The Icahn Institute for Genomics and Multiscale Biology, Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Trinity College Dublin-St. James's Hospital, Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario]-Offord Centre for Child Studies, Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), McLaughlin Centre, University of Toronto, BioFIG, Center for Biodiversity, Functional and Integrative Genomics, Department of Neurology, University of California [Los Angeles] (UCLA), University of California-University of California-David Geffen School of Medicine [Los Angeles], University of California-University of California, Fisico-Quimica Biologica, Universidade Federal do Rio de Janeiro (UFRJ), John P. Hussman Institute for Human Genomics, University of Miami [Coral Gables], Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Pathology and Laboratory Medicine, University of Pennsylvania [Philadelphia], Department of Pathology, Vanderbilt Brain Institute, Vanderbilt University School of Medicine [Nashville], Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University [Nashville]-Centers for Human Genetics Research and Molecular Neuroscience, Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital [Toronto, Canada] (MSH), Prevention & Cancer Control, Cancer Care Ontario, Department of Preventive Medicine, University of Southern California (USC), Department of Pediatrics, University of Alberta, School of Education, University of Birmingham [Birmingham], University of Oxford [Oxford]-Warneford Hospital, Octogone Unité de Recherche Interdisciplinaire (Octogone), Université Toulouse - Jean Jaurès (UT2J), Autism Research Unit, The Hospital for sick children [Toronto] (SickKids)-University of Toronto, Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Institute for Biomedical Imaging and Life Science, University of Coimbra [Portugal] (UC), Vanderbilt University [Nashville], Center for Autism and the Developing Brain (CADB), Weill Medical College of Cornell University [New York], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Institute of Health and Society, Newcastle University [Newcastle], Department of Child and Adolescent Psychiatry, Newcastle University [Newcastle]-Institute of Health & Society (Child & Adolescent Psychiatry), Child Developmental and Behavioral Unit, Hospital Nacional de Niños Dr Sáenz Herrera, Institute for Juvenile Research-University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Manchester Academic Health Sciences Centre, Gillberg Neuropsychiatry Centre [Göteborg, Sueden], Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg (GU), Institute of Child Health, University College of London [London] (UCL), Memorial University of Newfoundland [St. John's], Disciplines of Genetics and Medicine, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Institute of Psychiatry, King‘s College London, Institute of psychiatry, University of Washington [Seattle], Paediatric Neurodisability, King‘s College London-King's Health Partners, MRC Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London-The Institute of Psychiatry, University of British Columbia (UBC), Bloorview Research Institute, Division of Medical Genetics [Seattle], Departments of Biostatistics and Medicine, Battelle Center for Mathematical Medicine, Ohio State University [Columbus] (OSU)-Nationwide Children's Hospital, Institute of Neuroscience [Newcastle] (ION), Institutes of Neuroscience and Health and Society, Indiana University School of Medicine, Indiana University System-Indiana University System, The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Children’s Hospital of Philadelphia (CHOP ), Utah Autism Research Program, University of Utah Psychiatry Department, University of Miami School of Medicine, Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris [Pisa], Department of Psychiatry and Behavioral Sciences [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford School of Medicine [Stanford], Institute for Juvenile Research, University of Illinois [Chicago] (UIC), Department of Neuroscience, Main funders of the Autism Genome Project: Autism Speaks (USA), the Health Research Board (Ireland, AUT/2006/1, AUT/2006/2, PD/2006/48), the Medical Research Council (UK), the Hilibrand Foundation (USA), Genome Canada, the Ontario Genomics Institute, and the Canadian Institutes of Health Research (CIHR), Autism Genome Project Consortium, Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Oxford, University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], University of California (UC)-University of California (UC), University of Pennsylvania, University of Oxford-Warneford Hospital, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania-University of Pennsylvania-Children’s Hospital of Philadelphia (CHOP ), Betancur, Catalina, Instituto Nacional de Saude Dr Ricardo Jorge, Universidade Federal do Rio de Janeiro [Rio de Janeiro] (UFRJ), Laboratoire Analyse et Modélisation pour la Biologie et l'Environnement (LAMBE - UMR 8587), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Università di Bologna [Bologna] (UNIBO), Mount Sinai Hospital (MSH), University of Toronto-The Hospital for Sick Children, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Gillberg Neuropsychiatry Centre, University of Gothenburg (GU), Stanford University Medical School, Stanford University School of Medicine [Stanford], Stanford University [Stanford], Université de Toulouse (UT)-Université de Toulouse (UT), Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, Thiruvahindrapuram B, Xu X, Ziman R, Wang Z, Vorstman JA, Thompson A, Regan R, Pilorge M, Pellecchia G, Pagnamenta AT, Oliveira B, Marshall CR, Magalhaes TR, Lowe JK, Howe JL, Griswold AJ, Gilbert J, Duketis E, Dombroski BA, De Jonge MV, Cuccaro M, Crawford EL, Correia CT, Conroy J, Conceição IC, Chiocchetti AG, Casey JP, Cai G, Cabrol C, Bolshakova N, Bacchelli E, Anney R, Gallinger S, Cotterchio M, Casey G, Zwaigenbaum L, Wittemeyer K, Wing K, Wallace S, van Engeland H, Tryfon A, Thomson S, Soorya L, Rogé B, Roberts W, Poustka F, Mouga S, Minshew N, McInnes LA, McGrew SG, Lord C, Leboyer M, Le Couteur AS, Kolevzon A, Jiménez González P, Jacob S, Holt R, Guter S, Green J, Green A, Gillberg C, Fernandez BA, Duque F, Delorme R, Dawson G, Chaste P, Café C, Brennan S, Bourgeron T, Bolton PF, Bölte S, Bernier R, Baird G, Bailey AJ, Anagnostou E, Almeida J, Wijsman EM, Vieland VJ, Vicente AM, Schellenberg GD, Pericak-Vance M, Paterson AD, Parr JR, Oliveira G, Nurnberger JI, Monaco AP, Maestrini E, Klauck SM, Hakonarson H, Haines JL, Geschwind DH, Freitag CM, Folstein SE, Ennis S, Coon H, Battaglia A, Szatmari P, Sutcliffe JS, Hallmayer J, Gill M, Cook EH, Buxbaum JD, Devlin B, Gallagher L, Betancur C, and Scherer SW.
Subjects: Male, INTELLECTUAL DISABILITY, pathways, Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, Bioinformatics, DUPLICATIONS, Intellectual disability, Gene Regulatory Networks, Genetics(clinical), Copy-number variation, 10. No inequality, Child, GDI1, Genetics (clinical), Sequence Deletion, COPY NUMBER VARIANTS, Genetics, gene networks, Copy Number Variation, 3. Good health, Pedigree, Fragile X syndrome, Multigene Family, Female, Metabolic Networks and Pathways, de novo, DNA Copy Number Variations, autism, Biology, rare CNV, PHENOTYPE ONTOLOGY, Article, Structural variation, mental disorders, medicine, Humans, ddc:610, FRAGILE-X-SYNDROME, GENOME-WIDE ASSOCIATION, Gene, [SDV.GEN]Life Sciences [q-bio]/Genetics, HDAC4, SETD5, medicine.disease, CHD2, inherited, STRUCTURAL VARIATION, DELETIONS, DE-NOVO MUTATIONS, Child Development Disorders, Pervasive, Autism
Abstract: International audience; Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
Published: 2014
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47. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

Author: Anita Thapar, Lena Backlund, Lindsey Kent, Walter J. Muir, A. Jeremy Willsey, Sandra K. Loo, Michael Boehnke, Christa Lese Martin, Ania Korszun, Guiomar Oliveira, Veronica J. Vieland, Stephen W. Scherer, René S. Kahn, Darina Czamara, Jeremy R. Parr, Michael E. Goddard, Willem A. Nolen, Josep Antoni Ramos-Quiroga, Stephen Sanders, Karola Rehnstroem, Nelson B. Freimer, Erin N. Smith, Ann Olincy, Ingrid Melle, Myrna M. Weissman, James A. Knowles, William Byerley, Aravinda Chakravarti, Shaun Purcell, Jens Treutlein, Sebastian Zoellner, Hakon Hakonarson, Susanne Lucae, Markus M. Noethen, Ian B. Hickie, Marion Friedl, Srinivasa Thirumalai, Stephen Newhouse, Joseph Piven, Andrew M. McIntosh, Cathryn M. Lewis, Srdjan Djurovic, Francis J. McMahon, Ayman H. Fanous, Bernie Devlin, Steven A. McCarroll, Alan F. Schatzberg, Peter Szatmari, Marta Ribasés, C. Robert Cloninger, Brenda W.J.H. Penninx, Gerard van Grootheest, Phil Lee, Richard Anney, Elaine K. Green, Geraldine Dawson, Joseph A. Sergeant, Digby Quested, Magdalena Gross, Jack D. Barchas, Nicholas G. Martin, Timothy W. Yu, Jouke-Jan Hottenga, Mark Lathrop, Federica Tozzi, Martin Hautzinger, Alysa E. Doyle, Cinnamon S. Bloss, Sandra Meier, Louise Gailagher, David A. Collier, Farooq Amin, Michael C. Neale, Martin Schalling, Lieuwe de Haan, Bru Cormand, Falk W. Lohoff, Jennifer Crosbie, Howard J. Edenberg, Aarno Palotie, Johannes H. Smit, Robert Freedman, Katherine Gordon-Smith, Michele L. Pergadia, Enda M. Byrne, Hans-Christoph Steinhausen, Benjamin M. Neale, Anjali K. Henders, Michele T. Pato, Manuel Mattheisen, Urban Ösby, Edward M. Scolnick, Evaristus A. Nwulia, Fritz Poustka, Gonneke Willemsen, Andrew C. Heath, David St. Cair, Emma M. Quinn, I. Nicol Ferrier, John R. Kelsoe, Vanessa Hus, Andrew McQuillin, John P. Rice, William M. McMahon, Joseph Biederman, Danyu Lin, Wolfgang Maier, Frans G. Zitman, Josephine Elia, Nicholas J. Schork, Stéphane Jamain, Lizzy Rossin, Jubao Duan, Ingrid Agartz, Devin Absher, Jordan W. Smoller, Matthew W. State, Richard M. Myers, Shrikant Mane, Carlos N. Pato, William E. Bunney, Marian L. Hamshere, Manfred Uhr, Nicholas John Craddock, Astrid M. Vicente, Tobias Banaschewski, David Curtis, Anne Farmer, Scott D. Gordon, Anna K. Kaehler, Eric M. Morrow, Marcella Rietschel, Patrik K. E. Magnusson, Klaus-Peter Lesch, Rebecca McKinney, Jana Strohmaier, Thomas F. Wienker, Pablo V. Gejman, Douglas Blackwood, Maria Helena Pinto de Azevedo, Tiffany A. Greenwood, Don H. Linszen, Daniel L. Koller, Richard Bruggeman, Vinay Puri, Naomi R. Wray, Stanley J. Watson, Elena Maestrini, Valentina Moskvina, Frank Dudbridge, Danielle Posthuma, Edward G. Jones, Lambertus Klei, Sarah E. Bergen, Fan Meng, Steven P. Hamilton, Guy A. Rouleau, Pierandrea Muglia, Mikael Landén, Stephanie H. Witt, Laramie E. Duncan, Stanley Zammit, Judith A. Badner, Florian Holsboer, Eco J. C. de Geus, Daniel Moreno-De-Luca, Benjamin S. Pickard, Gunnar Morken, Michael Conlon O'Donovan, Michael Steffens, Kathryn Roeder, Dorret I. Boomsma, Paul D. Shilling, Stephan Ripke, Nigel Williams, Jeremy M. Silverman, David Craig, Mark J. Daly, Michael Bauer, Detelina Grozeva, Markus J. Schwarz, Peter Holmans, Hugh Gurling, T. Scott Stroup, Aribert Rothenberger, Gary Donohoe, Eric Fombonne, Joseph D. Buxbaum, Matthew Flicldnger, Bryan J. Mowry, Thomas Hansen, Ina Giegling, Grant W. Montgomery, Caroline M. Nievergelt, Susan L. Smalley, Jung-Ying Tzeng, David H. Ledbetter, Christopher A. Walsh, Gerard D. Schellenberg, Sarah E. Medland, Robert D. Oades, James B. Potash, Dan E. Arking, Johannes Schumacher, Michael Gill, James J. McGough, Jennifer L. Moran, Donald W. Black, Sian Caesar, Neelroop N. Parikshak, Ian W. Craig, Sabine M. Klauck, Wade H. Berrettini, T. Foroud, Peter P. Zandi, Inez Myin-Germeys, Marcus Ising, Sven Cichon, Alexandre A. Todorov, Mònica Bayés, Thomas Werge, Susan L. Slager, Stanley I. Shyn, Jim van Os, Derek W. Morris, Douglas M. Ruderfer, Thomas W. Muehleisen, Matthew C. Keller, Susmita Datta, Ian Jones, John B. Vincent, James L. Kennedy, Anthony P. Monaco, Jianxin Shi, Dale R. Nyholt, Bruno Etain, Christine Fraser, Paul Cormican, Miguel Casas, Radhika Kandaswamy, Gerome Breen, Stephen V. Faraone, Jonna Kuntsi, Thomas Bettecken, Witte J.G. Hoogendijk, Nancy G. Buccola, Franziska Degenhardt, Lyudmila Georgieva, Marion Leboyer, Alan R. Sanders, John Strauss, Dan Rujescu, Russell Schachar, Helena Medeiros, Lisa Jones, Peter M. Visscher, Lauren A. Weiss, René Breuer, John I. Nurnberger, Andreas Reif, Phoenix Kwan, Vihra Milanova, Chunyu Liu, Martin A. Kohli, Donald J. MacIntyre, Nicholas Bass, Khalid Choudhury, Edwin H. Cook, Catherine Lord, Andrew D. Paterson, Jobst Meyer, Richard P. Ebstein, Zhaoming Zhao, Niklas Laengstroem, Thomas G. Schulze, Peter Propping, Wei Xu, Robert C. Thompson, Kimberly Chambert, Jonathan Pimm, Ivan Nikolov, Pamela A. F. Madden, Kevin A. McGhee, Jacob Lawrence, Jan K. Buitelaar, Andres Ingason, Christine M. Freitag, Robert Krasucki, Wiepke Cahn, Rita M. Cantor, Christina M. Hultman, Melvin G. McInnis, Catalina Betancur, Eftichia Duketis, Michael T. Murtha, Thomas H. Wassink, Philip Asherson, John S. Witte, Elaine Kenny, Edmund J.S. Sonuga-Barke, Lydia Krabbendam, Line Olsen, Agatino Battaglia, Laura J. Scott, Annette M. Hartmann, Yunjung Kim, Richard O. Day, Edwin J. C. G. van den Oord, Ole A. Andreassen, Herbert Roeyers, Michael John Owen, Colm O'Dushlaine, Peng Zhang, Morten Mattingsdal, Michael L. Cuccaro, Margaret A. Pericak-Vance, Joachim Hallmayer, Jun Li, Pamela B. Mahon, Elisabeth B. Binder, William A. Scheftner, Daniel H. Geschwind, Christel M. Middeldorp, Josef Frank, Keith Matthews, Jennifer K. Lowe, Paul Lichtenstein, Verneri Anttila, Pamela Sklar, Szabocls Szelinger, Roel A. Ophoff, Peter McGuffin, Stefan Herms, Bettina Konte, George Kirov, Hilary Coon, Maria Hipolito, Louise Frisén, Kenneth S. Kendler, Frank Bellivier, James S. Sutdiffe, Jeffrey A. Lieberman, Todd Lencz, Susanne Hoefels, Alan W. McLean, Barbara Franke, Huda Akil, Soumya Raychaudhuri, Ellen M. Wijsman, Vishwajit L. Nimgaonkar, Roy H. Perlis, Patrick J. McGrath, Susan L. Santangelo, William Coryell, Henrik B. Rasmussen, Weihua Guan, William Lawson, Elliot S. Gershon, Sean Ennis, Aiden Corvin, Allan H. Young, Thomas B. Barrett, Jonathan L. Haines, Douglas F. Levinson, Ana Miranda, Anil K. Malhotra, S. Hong Lee, Stan F. Nelson, Anthony J. Bailey, Patrick F. Sullivan, Dorothy E. Grice, Lefkos T. Middleton, Bertram Mueller-Myhsok, Michael R. Barnes, Adebayo Anjorin, O'Dushlaine, C, Rossin, L, Lee, Ph, Duncan, L, Parikshak, Nn, Newhouse, S, Ripke, S, Neale, Bm, Purcell, Sm, Posthuma, D, Nurnberger, Ji, Lee, Sh, Faraone, Sv, Perlis, Rh, Mowry, Bj, Thapar, A, Goddard, Me, Witte, J, Absher, D, Agartz, I, Akil, H, Amin, F, Andreassen, Oa, Anjorin, A, Anney, R, Anttila, V, Arking, De, Asherson, P, Azevedo, Mh, Backlund, L, Badner, Ja, Bailey, Aj, Banaschewski, T, Barchas, Jd, Barnes, Mr, Barrett, Tb, Bass, N, Battaglia, A, Bauer, M, Bayés, M, Bellivier, F, Bergen, Se, Berrettini, W, Betancur, C, Bettecken, T, Biederman, J, Binder, Eb, Black, Dw, Blackwood, Dh, Bloss, C, Boehnke, M, Boomsma, Di, Breuer, R, Bruggeman, R, Cormican, P, Buccola, Ng, Buitelaar, Jk, Bunney, We, Buxbaum, Jd, Byerley, Wf, Byrne, Em, Caesar, S, Cahn, W, Cantor, Rm, Casas, M, Chakravarti, A, Chambert, K, Choudhury, K, Cichon, S, Mattheisen, M, Cloninger, Cr, Collier, Da, Cook, Eh, Coon, H, Cormand, B, Corvin, A, Coryell, Wh, Craig, Dw, Craig, Iw, Crosbie, J, Cuccaro, Ml, Curtis, D, Czamara, D, Datta, S, Dawson, G, Day, R, De Geus, Ej, Degenhardt, F, Djurovic, S, Donohoe, Gj, Doyle, Ae, Duan, J, Dudbridge, F, Duketis, E, Ebstein, Rp, Edenberg, Hj, Elia, J, Ennis, S, Etain, B, Fanous, A, Farmer, Ae, Ferrier, In, Flickinger, M, Fombonne, E, Foroud, T, Frank, J, Franke, B, Fraser, C, Freedman, R, Freimer, Nb, Freitag, Cm, Friedl, M, Frisén, L, Gallagher, L, Gejman, Pv, Georgieva, L, Gershon, E, Giegling, I, Gill, M, Gordon, Sd, Gordon-Smith, K, Green, Ek, Greenwood, Ta, Grice, De, Gross, M, Grozeva, D, Guan, W, Gurling, H, De Haan, L, Haines, Jl, Hakonarson, H, Hallmayer, J, Hamilton, Sp, Hamshere, Ml, Hansen, Tf, Hartmann, Am, Hautzinger, M, Heath, Ac, Henders, Ak, Herms, S, Hickie, Ib, Hipolito, M, Hoefels, S, Holsboer, F, Hoogendijk, Wj, Hottenga, Jj, Hultman, Cm, Hus, V, Ingason, A, Ising, M, Jamain, S, Jones, Eg, Jones, I, Jones, L, Tzeng, Jy, Kähler, Ak, Kahn, R, Kandaswamy, R, Keller, Mc, Kennedy, Jl, Kenny, E, Kent, L, Kim, Y, Kirov, Gk, Klauck, Sm, Klei, L, Knowles, Ja, Kohli, Ma, Koller, Dl, Konte, B, Korszun, A, Krabbendam, L, Krasucki, R, Kuntsi, J, Kwan, P, Landén, M, Längström, N, Lathrop, M, Lawrence, J, Lawson, Wb, Leboyer, M, Ledbetter, Dh, Lencz, T, Lesch, Kp, Levinson, Df, Lewis, Cm, Li, J, Lichtenstein, P, Lieberman, Ja, Lin, Dy, Linszen, Dh, Liu, C, Lohoff, Fw, Loo, Sk, Lord, C, Lowe, Jk, Lucae, S, Macintyre, Dj, Madden, Pa, Maestrini, E, Magnusson, Pk, Mahon, Pb, Maier, W, Malhotra, Ak, Mane, Sm, Martin, Cl, Martin, Ng, Matthews, K, Mattingsdal, M, Mccarroll, Sa, Mcghee, Ka, Mcgough, Jj, Mcgrath, Pj, Mcguffin, P, Mcinnis, Mg, Mcintosh, A, Mckinney, R, Mclean, Aw, Mcmahon, Fj, Mcmahon, Wm, Mcquillin, A, Medeiros, H, Medland, Se, Meier, S, Melle, I, Meyer, J, Middeldorp, Cm, Middleton, L, Milanova, V, Miranda, A, Monaco, A, Montgomery, Gw, Moran, Jl, Moreno-De-Luca, D, Morken, G, Morris, Dw, Morrow, Em, Moskvina, V, Muglia, P, Mühleisen, Tw, Muir, Wj, Müller-Myhsok, B, Murtha, M, Myers, Rm, Myin-Germeys, I, Neale, Mc, Nelson, Sf, Nievergelt, Cm, Nikolov, I, Nimgaonkar, V, Nolen, Wa, Nöthen, Mm, Nwulia, Ea, Nyholt, Dr, Oades, Rd, Olincy, A, Oliveira, G, Olsen, L, Ophoff, Ra, Osby, U, Owen, Mj, Palotie, A, Parr, Jr, Paterson, Ad, Pato, Cn, Pato, Mt, Penninx, Bw, Pergadia, Ml, Pericak-Vance, Ma, Pickard, B, Pimm, J, Piven, J, Potash, Jb, Poustka, F, Propping, P, Puri, V, Quested, Dj, Quinn, Em, Ramos-Quiroga, Ja, Rasmussen, Hb, Raychaudhuri, S, Rehnström, K, Reif, A, Ribasés, M, Rice, Jp, Rietschel, M, Roeder, K, Roeyers, H, Rothenberger, A, Rouleau, G, Ruderfer, D, Rujescu, D, Sanders, Ar, Sanders, Sj, Santangelo, Sl, Sergeant, Ja, Schachar, R, Schalling, M, Schatzberg, Af, Scheftner, Wa, Schellenberg, Gd, Scherer, Sw, Schork, Nj, Schulze, Tg, Schumacher, J, Schwarz, M, Scolnick, E, Scott, Lj, Shi, J, Shilling, Pd, Shyn, Si, Silverman, Jm, Slager, Sl, Smalley, Sl, Smit, Jh, Smith, En, Sonuga-Barke, Ej, St Clair, D, State, M, Steffens, M, Steinhausen, Hc, Strauss, J, Strohmaier, J, Stroup, T, Sutcliffe, J, Szatmari, P, Szelinger, S, Thirumalai, S, Thompson, Rc, Todorov, Aa, Tozzi, F, Treutlein, J, Uhr, M, van den Oord, Jc, Van Grootheest, G, Van Os, J, Vicente, A, Vieland, Vj, Vincent, Jb, Visscher, Pm, Walsh, Ca, Wassink, Th, Watson, Sj, Weissman, Mm, Werge, T, Wienker, Tf, Wijsman, Em, Willemsen, G, Williams, N, Willsey, Aj, Witt, Sh, Xu, W, Young, Ah, Yu, Tw, Zammit, S, Zandi, Pp, Zhang, P, Zitman, Fg, Zöllner, S, Devlin, B, Kelsoe, Jr, Sklar, P, Daly, Mj, O'Donovan, Mc, Craddock, N, Kendler, K, Weiss, La, Wray, Nr, Zhao, Z, Geschwind, Dh, Sullivan, Pf, Smoller, Jw, Holmans, Pa, Breen, G., Génétique de l'autisme = Genetics of Autism (NPS-01), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Human genetics, Psychiatry, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, Child and Adolescent Psychiatry / Psychology, Epidemiology, Gastroenterology & Hepatology, Hematology, University of St Andrews. School of Medicine, University of St Andrews. Institute of Behavioural and Neural Sciences, Psychiatrie & Neuropsychologie, MUMC+: MA Psychiatrie (3), MUMC+: Hersen en Zenuw Centrum (3), RS: MHeNs - R2 - Mental Health, ANS - Amsterdam Neuroscience, Adult Psychiatry, Child Psychiatry, Universitat de Barcelona, Perceptual and Cognitive Neuroscience (PCN), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Complex Trait Genetics, Biological Psychology, Educational Neuroscience, Clinical Neuropsychology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, LEARN! - Social cognition and learning, LEARN! - Brain, learning and development, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), O'Dushlaine, Colm, Rossin, Lizzy, Lee, Phil H, Duncan, Laramie, Lee, S Hong, Breen, Gerome, International Inflammatory Bowel Disease Genetics Consortium (IIBDGC), Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium, and Myin-Germeys, Inez
Subjects: Netherlands Twin Register (NTR), Statistical methods, Autism, Medizin, LOCI, Genome-wide association study, heritability, Genome-wide association studies, Histones, Genètica mèdica, 0302 clinical medicine, Histone methylation, Databases, Genetic, 2.1 Biological and endogenous factors, Psychology, GWAS, Aetiology, Psychiatric genetics, R2C, bipolar disorder, Psychiatry, 0303 health sciences, Disorders, Loci, Depression, General Neuroscience, Mental Disorders, Medical genetics, METHYLATION, Brain, 3rd-DAS, Serious Mental Illness, Psychiatric Disorders, 3. Good health, Histone, Mental Health, Schizophrenia, Mental Disorder, Cognitive Sciences, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Promoters, BDC, BURDEN, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, Human, Signal Transduction, medicine.medical_specialty, DISORDERS, Genomics, Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium, Burden, Biology, Methylation, Article, Biological pathway, PROMOTERS, 03 medical and health sciences, Databases, Genetic, medicine, Genetics, Humans, Genetic Predisposition to Disease, histone methylation, Bipolar disorder, Psiquiatria, AUTISM, 030304 developmental biology, Genetic association, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Neurology & Neurosurgery, Neuroscience (all), Human Genome, Neurosciences, medicine.disease, Brain Disorders, Good Health and Well Being, DE-NOVO MUTATIONS, Perturbações do Desenvolvimento Infantil e Saúde Mental, RC0321, Genome-wide Association Studies, De-novo mutations, major depression, Neuroscience, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: G.B. and S.N. acknowledge funding support for this work from the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. P.H.L. is supported by US National Institute of Mental Health (NIMH) grant K99MH101367. Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders. Postprint
Published: 2015

48. Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments

Author: Anne Claude Tabet, Françoise Devillard, Christelle M. Durand, Dominique Bonneau, Caroline Schluth-Bolard, Hugo Peyre, Frédérique Amsellem, Jennifer L. Howe, Brigitte Assouline, Laurence Perrin, Patrick Edery, Gudrun A. Rappold, Alexis Brice, Tobias M. Boeckers, Kevin Mouzat, Mary Coleman, Diana Zelenika, Guy A. Rouleau, Christel Depienne, Alexandra Afenjar, Pilar Galan, Peter Szatmari, Coline Stordeur, Fabienne Giuliano, Thomas Bourgeron, Delphine Héron, Anthony P. Monaco, Aurélia Jacquette, Marion Leboyer, Elena Maestrini, Roberto Toro, Anne Polge, Serge Lumbroso, Richard Delorme, Maria Råstam, François Rivier, Richard Holt, Stephen W. Scherer, Jessica Guibert, Elodie Ey, Dalila Pinto, Christopher Gillberg, Béatrice Regnault, Fanny Laffargue, Claire S. Leblond, Julie Gauthier, Nathalie Lemière, James Lespinasse, Alexandre Mathieu, Michael J. Schmeisser, Jean Chiesa, Agnès Rastetter, Marc Delepine, Catalina Betancur, I. Carina Gillberg, Daisuke Sato, Mark Lathrop, Caroline Nava, Damien Sanlaville, Guillaume Huguet, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Biochimie, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Laboratoire de diagnotic moléculaire, CHU Sainte Justine [Montréal], Service de génétique médicale, Hôpital l'Archet, Service de Psychiatrie de l'Enfant et de l'Adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Departments of Psychiatry, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Seaver Autism Center-, The Mindich Child Health & Development Institute, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Laboratoire de sciences cognitives et psycholinguistique (LSCP), Département d'Etudes Cognitives - ENS Paris (DEC), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS), Fondation FondaMental [Créteil], Department of Clinical Sciences, Lund University [Lund], Gillberg Neuropsychiatry Centre [Göteborg, Sueden], Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg (GU), Department of Molecular Human Genetics, Universität Heidelberg [Heidelberg] = Heidelberg University, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-Hôpital Couple-Enfant, Unité Pédopsychiatrique et Neuropédiatrique de Diagnostic et d'Evaluation des Troubles Envahissants du Développement, Centre Alpin de DIagnostic Précoce de l'Autisme - CADIPA-Centre Hospitalier Alpes Isère, Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Département de Génétique Chromosomique, Bâtiment Hôtel Dieu - Centre Hospitalier de Chambéry, Laboratoire de Cytogénétique, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Biochimie et Génétique, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Génotypage des Eucaryotes (Plate-Forme), Institut Pasteur [Paris] (IP), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut for Anatomy and Cell Biology, Universität Ulm - Ulm University [Ulm, Allemagne], Foundation for Autism Research, Center of Excellence in Neuroscience, CHU de Montréal, Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Institute of Child Health, University College of London [London] (UCL), This work was funded by the Institut Pasteur, CNRS, INSERM, AP-HP, University Paris Diderot, the Bettencourt-Schueller foundation, the Orange foundation, the FondaMental foundation, the Conny-Maeva foundation, the Cognacq-Jay foundation, the ANR (ANR-08-MNPS-037-01 - SynGen), Neuron- ERANET (EUHF-AUTISM), the DFG (BO1718/3-1, 4-1) and Baustein L.SBN.0081., Leblond CS, Nava C, Polge A, Gauthier J, Huguet G, Lumbroso S, Giuliano F, Stordeur C, Depienne C, Mouzat K, Pinto D, Howe J, Lemière N, Durand CM, Guibert J, Ey E, Toro R, Peyre H, Mathieu A, Amsellem F, Rastam M, Gillberg IC, Rappold GA, Holt R, Monaco AP, Maestrini E, Galan P, Heron D, Jacquette A, Afenjar A, Rastetter A, Brice A, Devillard F, Assouline B, Laffargue F, Lespinasse J, Chiesa J, Rivier F, Bonneau D, Regnault B, Zelenika D, Delepine M, Lathrop M, Sanlaville D, Schluth-Bolard C, Edery P, Perrin L, Tabet AC, Schmeisser MJ, Boeckers TM, Coleman M, Sato D, Szatmari P, Scherer SW, Rouleau GA, Betancur C, Leboyer M, Gillberg C, Delorme R, Bourgeron T, Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Universität Heidelberg [Heidelberg], University of Oxford [Oxford], Unité Fonctionnelle de Génétique Clinique [CHU Pitié Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pasteur [Paris], Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurosciences Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon (CRNL), and Betancur, Catalina
Subjects: Male, Cancer Research, [SDV.GEN] Life Sciences [q-bio]/Genetics, medicine.disease_cause, GENE DELETION, 0302 clinical medicine, Cognition, Intellectual disability, Child, Genetics (clinical), Genetics, Psychiatry, Neurons, 0303 health sciences, Mutation, SDV:GEN, META-ANALYSIS, Penetrance, Hypotonia, 3. Good health, SHANK2, Autism spectrum disorder, Female, medicine.symptom, Research Article, lcsh:QH426-470, DNA Copy Number Variations, Nerve Tissue Proteins, Biology, 03 medical and health sciences, Intellectual Disability, mental disorders, medicine, Humans, Clinical significance, AUTISM, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Biology and Life Sciences, Human Genetics, medicine.disease, lcsh:Genetics, Child Development Disorders, Pervasive, Case-Control Studies, Synapses, Autism, Cognition Disorders, 030217 neurology & neurosurgery
Abstract: SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability—more than 1 in 50—warrant its consideration for mutation screening in clinical practice., Author Summary Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders. Mutations altering genes involved in the junction between brain cells have been repeatedly associated in ASD. For example, SHANK1, SHANK2 and SHANK3 emerged as one family of genes that are associated with ASD. However, little was known about the number of patients carrying these mutations and the clinical outcome. Here, we performed a new genetic screen of SHANK mutations and these results were analyzed in combination with those of the literature. In summary, SHANK mutations account for ∼1% of patients with ASD and were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. Given the high frequency and impact of SHANK3 mutations in individuals with ASD and intellectual disability—more than 1 in 50—this gene should be screened for mutations in clinical practice.
Published: 2014

49. Copy number variation in obsessive-compulsive disorder and tourette syndrome: a cross-disorder study

Author: McGrath, Lauren M, Yu, Dongmei, Marshall, Christian, Davis, Lea K, Thiruvahindrapuram, Bhooma, Li, Bingbin, Cappi, Carolina, Gerber, Gloria, Wolf, Aaron, Schroeder, Frederick A, Osiecki, Lisa, O'Dushlaine, Colm, Kirby, Andrew, Illmann, Cornelia, Haddad, Stephen, Gallagher, Patience, Fagerness, Jesen A, Barr, Cathy L, Bellodi, Laura, Benarroch, Fortu, Bienvenu, O Joseph, Black, Donald W, Bloch, Michael H, Bruun, Ruth D, Budman, Cathy L, Camarena, Beatriz, Cath, Danielle C, Cavallini, Maria C, Chouinard, Sylvain, Coric, Vladimir, Cullen, Bernadette, Delorme, Richard, Denys, Damiaan, Derks, Eske M, Dion, Yves, Rosário, Maria C, Eapen, Valsama, Evans, Patrick, Falkai, Peter, Fernandez, Thomas V, Garrido, Helena, Geller, Daniel, Grabe, Hans J, Grados, Marco A, Greenberg, Benjamin D, Gross-Tsur, Varda, Grünblatt, Edna, Heiman, Gary A, Hemmings, Sian M J, Herrera, Luis D, Hounie, Ana G, Jankovic, Joseph, Kennedy, James L, King, Robert A, Kurlan, Roger, Lanzagorta, Nuria, Leboyer, Marion, Leckman, James F, Lennertz, Leonhard, Lochner, Christine, Lowe, Thomas L, Lyon, Gholson J, Macciardi, Fabio, Maier, Wolfgang, McCracken, James T, McMahon, William, Murphy, Dennis L, Naarden, Allan L, Neale, Benjamin M, Nurmi, Erika, Pakstis, Andrew J, Pato, Michele T, Pato, Carlos N, Piacentini, John, Pittenger, Christopher, Pollak, Yehuda, Reus, Victor I, Richter, Margaret A, Riddle, Mark, Robertson, Mary M, Rosenberg, David, Rouleau, Guy A, Ruhrmann, Stephan, Sampaio, Aline S, Samuels, Jack, Sandor, Paul, Sheppard, Brooke, Singer, Harvey S, Smit, Jan H, Stein, Dan J, Tischfield, Jay A, Vallada, Homero, Veenstra-VanderWeele, Jeremy, Walitza, Susanne, Wang, Ying, Wendland, Jens R, Shugart, Yin Yao, Miguel, Euripedes C, Nicolini, Humberto, Oostra, Ben A, Moessner, Rainald, Wagner, Michael, Ruiz-Linares, Andres, Heutink, Peter, Nestadt, Gerald, Freimer, Nelson, Petryshen, Tracey, Posthuma, Danielle, Jenike, Michael A, Cox, Nancy J, Hanna, Gregory L, Brentani, Helena, Scherer, Stephen W, Arnold, Paul D, Stewart, S Evelyn, Mathews, Carol A, Knowles, James A, Cook, Edwin H, Pauls, David L, Wang, Kai, Scharf, Jeremiah M, Leerstoel Hout, Sub String Theory Cosmology and ElemPart, Experimental psychopathology, University of Zurich, Scharf, Jeremiah M, Leerstoel Hout, Sub String Theory Cosmology and ElemPart, Experimental psychopathology, Clinical Genetics, Child and Adolescent Psychiatry / Psychology, Artificial intelligence, Complex Trait Genetics, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Functional Genomics, AIMMS, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, ANS - Amsterdam Neuroscience, Adult Psychiatry, APH - Amsterdam Public Health, Netherlands Institute for Neuroscience (NIN), Mcgrath, Lm, Yu, D, Marshall, C, Davis, Lk, Thiruvahindrapuram, B, Li, B, Cappi, C, Gerber, G, Wolf, A, Schroeder, Fa, Osiecki, L, O'Dushlaine, C, Kirby, A, Illmann, C, Haddad, S, Gallagher, P, Fagerness, Ja, Barr, Cl, Bellodi, Laura, Benarroch, F, Bienvenu, Oj, Black, Dw, Bloch, Mh, Bruun, Rd, Budman, Cl, Camarena, B, Cath, Dc, Cavallini, Mc, Chouinard, S, Coric, V, Cullen, B, Delorme, R, Denys, D, Derks, Em, Dion, Y, Rosário, Mc, Eapen, V, Evans, P, Falkai, P, Fernandez, Tv, Garrido, H, Geller, D, Grabe, Hj, Grados, Ma, Greenberg, Bd, Gross Tsur, V, Grünblatt, E, Heiman, Ga, Hemmings, Sm, Herrera, Ld, Hounie, Ag, Jankovic, J, Kennedy, Jl, King, Ra, Kurlan, R, Lanzagorta, N, Leboyer, M, Leckman, Jf, Lennertz, L, Lochner, C, Lowe, Tl, Lyon, Gj, Macciardi, F, Maier, W, Mccracken, Jt, Mcmahon, W, Murphy, Dl, Naarden, Al, Neale, Bm, Nurmi, E, Pakstis, Aj, Pato, Mt, Pato, Cn, Piacentini, J, Pittenger, C, Pollak, Y, Reus, Vi, Richter, Ma, Riddle, M, Robertson, Mm, Rosenberg, D, Rouleau, Ga, Ruhrmann, S, Sampaio, A, Samuels, J, Sandor, P, Sheppard, B, Singer, H, Smit, Jh, Stein, Dj, Tischfield, Ja, Vallada, H, Veenstra VanderWeele, J, Walitza, S, Wang, Y, Wendland, Jr, Shugart, Yy, Miguel, Ec, Nicolini, H, Oostra, Ba, Moessner, R, Wagner, M, Ruiz Linares, A, Heutink, P, Nestadt, G, Freimer, N, Petryshen, T, Posthuma, D, Jenike, Ma, Cox, Nj, Hanna, Gl, Brentani, H, Scherer, Sw, Arnold, Pd, Stewart, Se, Mathews, Ca, Knowles, Ja, Cook, Eh, Pauls, Dl, Wang, K, Scharf, J. M., Psychiatry, Human genetics, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, and EMGO - Mental health
Subjects: Oncology, Male, medicine.medical_specialty, diagnosis [Tourette Syndrome], Adolescent, DNA Copy Number Variations, Genome-wide association study, 610 Medicine & health, Tourette syndrome, Polymorphism, Single Nucleotide, behavioral disciplines and activities, Article, 2738 Psychiatry and Mental Health, SDG 3 - Good Health and Well-being, Obsessive compulsive, Genetic etiology, Internal medicine, mental disorders, Developmental and Educational Psychology, medicine, Humans, Genetic Predisposition to Disease, genetics, Copy-number variation, ddc:610, Genetics, genetics [Obsessive-Compulsive Disorder], 3204 Developmental and Educational Psychology, copy number variation, 10058 Department of Child and Adolescent Psychiatry, medicine.disease, 16p13.11, Diagnostic and Statistical Manual of Mental Disorders, obsessive-compulsive disorder, Psychiatry and Mental health, genetics [Tourette Syndrome], Schizophrenia, Autism, Female, Psychology, Genome-Wide Association Study, diagnosis [Obsessive-Compulsive Disorder]
Abstract: Objective Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large (>500 kb), rare (
Published: 2014

50. Cytogenetic Prognostication Within Medulloblastoma Subgroups

Author: Franck Bourdeaut, Michael K. Cooper, Almos Klekner, Stefan Rutkowski, David Shih, Jeffrey R. Leonard, Simon Bailey, Concezio Di Rocco, Ulrich Schüller, Giuseppe Cinalli, Pim J. French, Cinzia Lavarino, Young Shin Ra, John Peacock, Yuan Yao, A. Sorana Morrissy, William A. Weiss, Nanne K. Kloosterhof, László Bognár, Pasqualino De Antonellis, Teiji Tominaga, Stephen W. Scherer, Paul A. Northcott, David T.W. Jones, Reid C. Thompson, Shenandoah Robinson, Marta Perek-Polnik, Boleslaw Lach, Massimo Zollo, Olivier Delattre, Jennifer A. Chan, Janet C. Lindsey, Xin Wang, Nada Jabado, Karel Zitterbart, David Malkin, Adi Rolider, Roger J. Packer, James M. Olson, Steffen Albrecht, Ji Yeoun Lee, Wiesława Grajkowska, Charles G. Eberhart, Marcel Kool, Vijay Ramaswamy, Seung-Ki Kim, Joanna J. Phillips, Andrey Korshunov, Michael D. Taylor, Florence M.G. Cavalli, Luca Massimi, Xiaochong Wu, Maryam Fouladi, Peter Hauser, Xing Fan, Steven C. Clifford, Leos Kren, Carmen de Torres, Erna M.C. Michiels, Adrian M. Dubuc, Amar Gajjar, Livia Garzia, Eric Bouffet, Ian F. Pollack, Marc Remke, Jaume Mora, Claudia C. Faria, Miklós Garami, Erwin G. Van Meir, Byung Kyu Cho, Karin M. Muraszko, Joshua B. Rubin, Anne Jouvet, Stefan M. Pfister, Nalin Gupta, Johan M. Kros, Shin Jung, Yoon Jae Cho, Rajeev Vibhakar, Linda M. Liau, Stephen C. Mack, Scott L. Pomeroy, Betty Luu, Cynthia Hawkins, Ali G. Saad, Kyu-Chang Wang, Uri Tabori, Michelle Fèvre-Montange, Adam M. Fontebasso, Robert J. Wechsler-Reya, Toshihiro Kumabe, James T. Rutka, François Doz, Shih, Dj, Northcott, Pa, Remke, M, Korshunov, A, Ramaswamy, V, Kool, M, Luu, B, Yao, Y, Wang, X, Dubuc, Am, Garzia, L, Peacock, J, Mack, Sc, Wu, X, Rolider, A, Morrissy, A, Cavalli, Fm, Jones, Dt, Zitterbart, K, Faria, Cc, Schüller, U, Kren, L, Kumabe, T, Tominaga, T, Shin Ra, Y, Garami, M, Hauser, P, Chan, Ja, Robinson, S, Bognár, L, Klekner, A, Saad, Ag, Liau, Lm, Albrecht, S, Fontebasso, A, Cinalli, G, DE ANTONELLIS, Pasqualino, Zollo, Massimo, Cooper, Mk, Thompson, Rc, Bailey, S, Lindsey, Jc, Di Rocco, C, Massimi, L, Michiels, Em, Scherer, Sw, Phillips, Jj, Gupta, N, Fan, X, Muraszko, Km, Vibhakar, R, Eberhart, Cg, Fouladi, M, Lach, B, Jung, S, Wechsler Reya, Rj, Fèvre Montange, M, Jouvet, A, Jabado, N, Pollack, If, Weiss, Wa, Lee, Jy, Cho, Bk, Kim, Sk, Wang, Kc, Leonard, Jr, Rubin, Jb, de Torres, C, Lavarino, C, Mora, J, Cho, Yj, Tabori, U, Olson, Jm, Gajjar, A, Packer, Rj, Rutkowski, S, Pomeroy, Sl, French, Pj, Kloosterhof, Nk, Kros, Jm, Van Meir, Eg, Clifford, Sc, Bourdeaut, F, Delattre, O, Doz, Ff, Hawkins, Ce, Malkin, D, Grajkowska, Wa, Perek Polnik, M, Bouffet, E, Rutka, Jt, Pfister, Sm, Taylor, M. d., Pulmonary Medicine, Pediatrics, Neurology, and Pathology
Subjects: Male, Cancer Research, Pathology, Risk Factors, Young adult, Stage (cooking), Pair 11, Child, In Situ Hybridization, Fluorescence, In Situ Hybridization, Cancer, Pediatric, screening and diagnosis, Tumor, Nuclear Proteins, ORIGINAL REPORTS, Orvostudományok, Prognosis, 3. Good health, Gene Expression Regulation, Neoplastic, Detection, Oncology, Child, Preschool, Predictive value of tests, Female, Patient Safety, Biotechnology, 4.2 Evaluation of markers and technologies, Human, medicine.medical_specialty, Pediatric Research Initiative, Adolescent, Pediatric Cancer, Clinical Sciences, Oncology and Carcinogenesis, Kruppel-Like Transcription Factors, Zinc Finger Protein Gli2, Extent of resection, Klinikai orvostudományok, Risk Assessment, Chromosomes, Fluorescence, Proto-Oncogene Proteins c-myc, Cytogenetics, Young Adult, Rare Diseases, Patient age, Clinical Research, Predictive Value of Tests, Biomarkers, Tumor, medicine, Humans, Hedgehog Proteins, Oncology & Carcinogenesis, Preschool, Proportional Hazards Models, Chromosomes, Human, Pair 14, Medulloblastoma, Neoplastic, business.industry, Proportional hazards model, Chromosomes, Human, Pair 11, Gene Expression Profiling, Pair 14, Reproducibility of Results, Infant, medicine.disease, Brain Disorders, 4.1 Discovery and preclinical testing of markers and technologies, Brain Cancer, Wnt Proteins, Gene Expression Regulation, Tissue Array Analysis, business, Biomarkers
Abstract: Purpose Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. Patients and Methods Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. Results Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. Conclusion Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.
Published: 2014

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