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1. PPIL4 is essential for brain angiogenesis and implicated in intracranial aneurysms in humans

Author

Barak, Tanyeri, Ristori, Emma, Ercan-Sencicek, A. Gulhan, Miyagishima, Danielle F., Nelson-Williams, Carol, Dong, Weilai, and Jin, Sheng Chih

Subjects
Gene mutations -- Health aspects, Intracranial aneurysms -- Diagnosis -- Care and treatment -- Risk factors, Neovascularization -- Methods -- Health aspects, Peptidyl transferases -- Testing, Biological sciences, Health
Abstract

Intracranial aneurysm (IA) rupture leads to subarachnoid hemorrhage, a sudden-onset disease that often causes death or severe disability. Although genome-wide association studies have identified common genetic variants that increase IA risk moderately, the contribution of variants with large effect remains poorly defined. Using whole-exome sequencing, we identified significant enrichment of rare, deleterious mutations in PPIL4, encoding peptidyl-prolyl cis-trans isomerase-like 4, in both familial and index IA cases. Ppil4 depletion in vertebrate models causes intracerebral hemorrhage, defects in cerebrovascular morphology and impaired Wnt signaling. Wild-type, but not IA-mutant, PPIL4 potentiates Wnt signaling by binding JMJD6, a known angiogenesis regulator and Wnt activator. These findings identify a novel PPIL4-dependent Wnt signaling mechanism involved in brain-specific angiogenesis and maintenance of cerebrovascular integrity and implicate PPIL4 gene mutations in the pathogenesis of IA. Genomic analyses in individuals with index and familial intracranial aneurysms and experiments in vertebrate models identify pathogenic variants in the PPIL4 gene implicated in cerebral angiogenesis and cerebrovascular integrity, through the Wnt signaling pathway., Author(s): Tanyeri Barak [sup.1] [sup.2] [sup.3] [sup.4] , Emma Ristori [sup.2] [sup.5] , A. Gulhan Ercan-Sencicek [sup.1] [sup.2] [sup.3] [sup.4] , Danielle F. Miyagishima [sup.1] [sup.2] [sup.3] [sup.4] , Carol [...]

Published
2021
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2. Contributors

Author

Al Sayed, Zeina R., primary, Aromalaran, Kelly, additional, Azad, Priti, additional, Bernardini, Laura, additional, Chen, Zhenyu, additional, Chennappan, Saravanakkumar, additional, Clegg, Dennis O., additional, Corli, Marzia, additional, Dwivedi, Ila, additional, Ercan-Sencicek, A. Gulhan, additional, Faynus, Mohamed A., additional, Forbes, Thomas A., additional, Gutmann, David H., additional, Haddad, Gabriel G., additional, Hamazaki, Takashi, additional, Hartigan, Kelly A., additional, Hattori, Taeka, additional, Hulot, Jean-Sébastien, additional, Imitola, Jaime, additional, Julian, Katherine, additional, Kontaridis, Maria Irene, additional, Leoni, Chiara, additional, Li, Xue-Jun, additional, Little, Melissa H., additional, Masurkar, Nihar, additional, Mou, Yongchao, additional, Onesimo, Roberta, additional, Pennuto, Maria, additional, Rosati, Jessica, additional, Schurr, Sarah V., additional, Shintaku, Haruo, additional, Sireno, Laura, additional, Turco, Elisa Maria, additional, Vescovi, Angelo Luigi, additional, Wu, Wei, additional, Yao, Hang, additional, Yu, Yang, additional, Zampino, Giuseppe, additional, and Zhao, Helen, additional

Published
2022
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4. Biallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly

Author

Li, Hongda, Bielas, Stephanie L, Zaki, Maha S, Ismail, Samira, Farfara, Dorit, Um, Kyongmi, Rosti, Rasim O, Scott, Eric C, Tu, Shu, Chi, Neil C, Gabriel, Stacey, Erson-Omay, Emine Z, Ercan-Sencicek, A Gulhan, Yasuno, Katsuhito, Çağlayan, Ahmet Okay, Kaymakçalan, Hande, Ekici, Barış, Bilguvar, Kaya, Gunel, Murat, and Gleeson, Joseph G

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, Brain Disorders, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Rare Diseases, Pediatric, Stem Cell Research, Intellectual and Developmental Disabilities (IDD), Stem Cell Research - Induced Pluripotent Stem Cell, Congenital Structural Anomalies, 2.1 Biological and endogenous factors, Aetiology, Neurological, Alleles, Apoptosis, Centrosome, Child, Child, Preschool, Cytokinesis, Female, Genes, Recessive, Humans, Infant, Newborn, Intracellular Signaling Peptides and Proteins, Male, Microcephaly, Mitosis, Mutation, Missense, Pedigree, Protein Serine-Threonine Kinases, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Cell division terminates with cytokinesis and cellular separation. Autosomal-recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by a reduction in brain and head size at birth in addition to non-progressive intellectual disability. MCPH is genetically heterogeneous, and 16 loci are known to be associated with loss-of-function mutations predominantly affecting centrosomal-associated proteins, but the multiple roles of centrosomes in cellular function has left questions about etiology. Here, we identified three families affected by homozygous missense mutations in CIT, encoding citron rho-interacting kinase (CIT), which has established roles in cytokinesis. All mutations caused substitution of conserved amino acid residues in the kinase domain and impaired kinase activity. Neural progenitors that were differentiated from induced pluripotent stem cells (iPSCs) derived from individuals with these mutations exhibited abnormal cytokinesis with delayed mitosis, multipolar spindles, and increased apoptosis, rescued by CRISPR/Cas9 genome editing. Our results highlight the importance of cytokinesis in the pathology of primary microcephaly.

Published
2016

5. Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases

Author

Perenthaler, Elena, Nikoncuk, Anita, Yousefi, Soheil, Berdowski, Woutje M., Alsagob, Maysoon, Capo, Ivan, van der Linde, Herma C., van den Berg, Paul, Jacobs, Edwin H., Putar, Darija, Ghazvini, Mehrnaz, Aronica, Eleonora, van IJcken, Wilfred F. J., de Valk, Walter G., Medici-van den Herik, Evita, van Slegtenhorst, Marjon, Brick, Lauren, Kozenko, Mariya, Kohler, Jennefer N., Bernstein, Jonathan A., Monaghan, Kristin G., Begtrup, Amber, Torene, Rebecca, Al Futaisi, Amna, Al Murshedi, Fathiya, Mani, Renjith, Al Azri, Faisal, Kamsteeg, Erik-Jan, Mojarrad, Majid, Eslahi, Atieh, Khazaei, Zaynab, Darmiyan, Fateme Massinaei, Doosti, Mohammad, Karimiani, Ehsan Ghayoor, Vandrovcova, Jana, Zafar, Faisal, Rana, Nuzhat, Kandaswamy, Krishna K., Hertecant, Jozef, Bauer, Peter, AlMuhaizea, Mohammed A., Salih, Mustafa A., Aldosary, Mazhor, Almass, Rawan, Al-Quait, Laila, Qubbaj, Wafa, Coskun, Serdar, Alahmadi, Khaled O., Hamad, Muddathir H. A., Alwadaee, Salem, Awartani, Khalid, Dababo, Anas M., Almohanna, Futwan, Colak, Dilek, Dehghani, Mohammadreza, Mehrjardi, Mohammad Yahya Vahidi, Gunel, Murat, Ercan-Sencicek, A. Gulhan, Passi, Gouri Rao, Cheema, Huma Arshad, Efthymiou, Stephanie, Houlden, Henry, Bertoli-Avella, Aida M., Brooks, Alice S., Retterer, Kyle, Maroofian, Reza, Kaya, Namik, van Ham, Tjakko J., and Barakat, Tahsin Stefan

Published
2020
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6. Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci

Author

Sanders, Stephan J, He, Xin, Willsey, A Jeremy, Ercan-Sencicek, A Gulhan, Samocha, Kaitlin E, Cicek, A Ercument, Murtha, Michael T, Bal, Vanessa H, Bishop, Somer L, Dong, Shan, Goldberg, Arthur P, Jinlu, Cai, Keaney, John F, Klei, Lambertus, Mandell, Jeffrey D, Moreno-De-Luca, Daniel, Poultney, Christopher S, Robinson, Elise B, Smith, Louw, Solli-Nowlan, Tor, Su, Mack Y, Teran, Nicole A, Walker, Michael F, Werling, Donna M, Beaudet, Arthur L, Cantor, Rita M, Fombonne, Eric, Geschwind, Daniel H, Grice, Dorothy E, Lord, Catherine, Lowe, Jennifer K, Mane, Shrikant M, Martin, Donna M, Morrow, Eric M, Talkowski, Michael E, Sutcliffe, James S, Walsh, Christopher A, Yu, Timothy W, Consortium, Autism Sequencing, Ledbetter, David H, Martin, Christa Lese, Cook, Edwin H, Buxbaum, Joseph D, Daly, Mark J, Devlin, Bernie, Roeder, Kathryn, and State, Matthew W

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Pediatric, Prevention, Biotechnology, Brain Disorders, Genetics, Mental Health, Intellectual and Developmental Disabilities (IDD), Human Genome, Autism, 2.1 Biological and endogenous factors, Aetiology, Mental health, Autism Spectrum Disorder, Female, Genetic Loci, Genetic Variation, Humans, Male, Protein Interaction Maps, Autism Sequencing Consortium, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1).

Published
2015

7. Homozygous loss of DIAPH1 is a novel cause of microcephaly in humans

Author

Ercan-Sencicek, A Gulhan, Jambi, Samira, Franjic, Daniel, Nishimura, Sayoko, Li, Mingfeng, El-Fishawy, Paul, Morgan, Thomas M, Sanders, Stephan J, Bilguvar, Kaya, Suri, Mohnish, Johnson, Michele H, Gupta, Abha R, Yuksel, Zafer, Mane, Shrikant, Grigorenko, Elena, Picciotto, Marina, Alberts, Arthur S, Gunel, Murat, Šestan, Nenad, and State, Matthew W

Subjects
Biochemistry and Cell Biology, Genetics, Biological Sciences, Pediatric, Neurosciences, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Aetiology, 2.1 Biological and endogenous factors, Adaptor Proteins, Signal Transducing, Adolescent, Adult, Animals, Brain, Carrier Proteins, Cell Line, Child, Child, Preschool, Codon, Nonsense, Female, Formins, Homozygote, Humans, Infant, Male, Mice, Microcephaly, Pedigree, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

The combination of family-based linkage analysis with high-throughput sequencing is a powerful approach to identifying rare genetic variants that contribute to genetically heterogeneous syndromes. Using parametric multipoint linkage analysis and whole exome sequencing, we have identified a gene responsible for microcephaly (MCP), severe visual impairment, intellectual disability, and short stature through the mapping of a homozygous nonsense alteration in a multiply-affected consanguineous family. This gene, DIAPH1, encodes the mammalian Diaphanous-related formin (mDia1), a member of the diaphanous-related formin family of Rho effector proteins. Upon the activation of GTP-bound Rho, mDia1 generates linear actin filaments in the maintenance of polarity during adhesion, migration, and division in immune cells and neuroepithelial cells, and in driving tangential migration of cortical interneurons in the rodent. Here, we show that patients with a homozygous nonsense DIAPH1 alteration (p.Gln778*) have MCP as well as reduced height and weight. diap1 (mDia1 knockout (KO))-deficient mice have grossly normal body and brain size. However, our histological analysis of diap1 KO mouse coronal brain sections at early and postnatal stages shows unilateral ventricular enlargement, indicating that this mutant mouse shows both important similarities as well as differences with human pathology. We also found that mDia1 protein is expressed in human neuronal precursor cells during mitotic cell division and has a major impact in the regulation of spindle formation and cell division.

Published
2015

8. De Novo Insertions and Deletions of Predominantly Paternal Origin Are Associated with Autism Spectrum Disorder

Author

Dong, Shan, Walker, Michael F, Carriero, Nicholas J, DiCola, Michael, Willsey, A Jeremy, Ye, Adam Y, Waqar, Zainulabedin, Gonzalez, Luis E, Overton, John D, Frahm, Stephanie, Keaney, John F, Teran, Nicole A, Dea, Jeanselle, Mandell, Jeffrey D, Bal, Vanessa Hus, Sullivan, Catherine A, DiLullo, Nicholas M, Khalil, Rehab O, Gockley, Jake, Yuksel, Zafer, Sertel, Sinem M, Ercan-Sencicek, A Gulhan, Gupta, Abha R, Mane, Shrikant M, Sheldon, Michael, Brooks, Andrew I, Roeder, Kathryn, Devlin, Bernie, State, Matthew W, Wei, Liping, and Sanders, Stephan J

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Autism, Human Genome, Intellectual and Developmental Disabilities (IDD), Brain Disorders, Mental Health, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Mental health, Child, Child Development Disorders, Pervasive, DNA, DNA-Binding Proteins, Female, Fragile X Mental Retardation Protein, Frameshift Mutation, GTP-Binding Proteins, Humans, Male, Nerve Tissue Proteins, Pedigree, Phenotype, Sequence Deletion, Sex Factors, Biochemistry and Cell Biology, Medical Physiology, Biological sciences
Abstract

Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single-nucleotide variants (SNVs) to autism spectrum disorder (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. By applying a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR = 1.6; 95% CI = 1.0-2.7; p = 0.03), are more common in female probands (p = 0.02), are enriched among genes encoding FMRP targets (p = 6 × 10(-9)), and arise predominantly on the paternal chromosome (p < 0.001). On the basis of mutation rates in probands versus unaffected siblings, we conclude that de novo frameshift indels contribute to risk in approximately 3% of individuals with ASD. Finally, by observing clustering of mutations in unrelated probands, we uncover two ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release.

Published
2014

9. Histidine Decarboxylase Deficiency Causes Tourette Syndrome: Parallel Findings in Humans and Mice

Author

Baldan, Lissandra Castellan, Williams, Kyle A, Gallezot, Jean-Dominique, Pogorelov, Vladimir, Rapanelli, Maximiliano, Crowley, Michael, Anderson, George M, Loring, Erin, Gorczyca, Roxanne, Billingslea, Eileen, Wasylink, Suzanne, Panza, Kaitlyn E, Ercan-Sencicek, A Gulhan, Krusong, Kuakarun, Leventhal, Bennett L, Ohtsu, Hiroshi, Bloch, Michael H, Hughes, Zoë A, Krystal, John H, Mayes, Linda, de Araujo, Ivan, Ding, Yu-Shin, State, Matthew W, and Pittenger, Christopher

Subjects
Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Genetics, Neurosciences, Brain Disorders, Neurodegenerative, Tourette Syndrome, 2.1 Biological and endogenous factors, Aetiology, Adolescent, Adult, Amphetamine, Animals, Brain, Child, Dopamine Agonists, Dopamine Antagonists, Exploratory Behavior, Female, Histidine Decarboxylase, Humans, Male, Maze Learning, Mice, Mice, Knockout, Middle Aged, Mutation, Oxazines, Raclopride, Radionuclide Imaging, Stereotyped Behavior, Time Factors, Tryptophan, Young Adult, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Tourette syndrome (TS) is characterized by tics, sensorimotor gating deficiencies, and abnormalities of cortico-basal ganglia circuits. A mutation in histidine decarboxylase (Hdc), the key enzyme for the biosynthesis of histamine (HA), has been implicated as a rare genetic cause. Hdc knockout mice exhibited potentiated tic-like stereotypies, recapitulating core phenomenology of TS; these were mitigated by the dopamine (DA) D2 antagonist haloperidol, a proven pharmacotherapy, and by HA infusion into the brain. Prepulse inhibition was impaired in both mice and humans carrying Hdc mutations. HA infusion reduced striatal DA levels; in Hdc knockout mice, striatal DA was increased and the DA-regulated immediate early gene Fos was upregulated. DA D2/D3 receptor binding was altered both in mice and in humans carrying the Hdc mutation. These data confirm histidine decarboxylase deficiency as a rare cause of TS and identify HA-DA interactions in the basal ganglia as an important locus of pathology.

Published
2014

10. Coexpression Networks Implicate Human Midfetal Deep Cortical Projection Neurons in the Pathogenesis of Autism

Author

Willsey, A Jeremy, Sanders, Stephan J, Li, Mingfeng, Dong, Shan, Tebbenkamp, Andrew T, Muhle, Rebecca A, Reilly, Steven K, Lin, Leon, Fertuzinhos, Sofia, Miller, Jeremy A, Murtha, Michael T, Bichsel, Candace, Niu, Wei, Cotney, Justin, Ercan-Sencicek, A Gulhan, Gockley, Jake, Gupta, Abha R, Han, Wenqi, He, Xin, Hoffman, Ellen J, Klei, Lambertus, Lei, Jing, Liu, Wenzhong, Liu, Li, Lu, Cong, Xu, Xuming, Zhu, Ying, Mane, Shrikant M, Lein, Ed S, Wei, Liping, Noonan, James P, Roeder, Kathryn, Devlin, Bernie, Sestan, Nenad, and State, Matthew W

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Neurosciences, Mental Health, Intellectual and Developmental Disabilities (IDD), Pediatric, Brain Disorders, Clinical Research, Autism, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Neurological, Mental health, Animals, Brain, Child Development Disorders, Pervasive, Exome, Female, Fetus, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Mice, Mutation, Neurons, Prefrontal Cortex, Sequence Analysis, DNA, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Autism spectrum disorder (ASD) is a complex developmental syndrome of unknown etiology. Recent studies employing exome- and genome-wide sequencing have identified nine high-confidence ASD (hcASD) genes. Working from the hypothesis that ASD-associated mutations in these biologically pleiotropic genes will disrupt intersecting developmental processes to contribute to a common phenotype, we have attempted to identify time periods, brain regions, and cell types in which these genes converge. We have constructed coexpression networks based on the hcASD "seed" genes, leveraging a rich expression data set encompassing multiple human brain regions across human development and into adulthood. By assessing enrichment of an independent set of probable ASD (pASD) genes, derived from the same sequencing studies, we demonstrate a key point of convergence in midfetal layer 5/6 cortical projection neurons. This approach informs when, where, and in what cell types mutations in these specific genes may be productively studied to clarify ASD pathophysiology.

Published
2013

11. Mutations in BCKD-kinase Lead to a Potentially Treatable Form of Autism with Epilepsy

Author

Novarino, Gaia, El-Fishawy, Paul, Kayserili, Hulya, Meguid, Nagwa A, Scott, Eric M, Schroth, Jana, Silhavy, Jennifer L, Kara, Majdi, Khalil, Rehab O, Ben-Omran, Tawfeg, Ercan-Sencicek, A Gulhan, Hashish, Adel F, Sanders, Stephan J, Gupta, Abha R, Hashem, Hebatalla S, Matern, Dietrich, Gabriel, Stacey, Sweetman, Larry, Rahimi, Yasmeen, Harris, Robert A, State, Matthew W, and Gleeson, Joseph G

Subjects
Autism, Pediatric, Neurodegenerative, Behavioral and Social Science, Intellectual and Developmental Disabilities (IDD), Brain Disorders, Neurosciences, Epilepsy, Genetics, Mental Health, Aetiology, 2.1 Biological and endogenous factors, Neurological, 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide), Adolescent, Amino Acids, Branched-Chain, Animals, Arginine, Autistic Disorder, Base Sequence, Brain, Child, Child, Preschool, Diet, Female, Homozygote, Humans, Intellectual Disability, Male, Mice, Mice, Knockout, Molecular Sequence Data, Mutation, Pedigree, Phosphorylation, Protein Folding, Protein Structure, Tertiary, RNA, Messenger, Young Adult, General Science & Technology
Abstract

Autism spectrum disorders are a genetically heterogeneous constellation of syndromes characterized by impairments in reciprocal social interaction. Available somatic treatments have limited efficacy. We have identified inactivating mutations in the gene BCKDK (Branched Chain Ketoacid Dehydrogenase Kinase) in consanguineous families with autism, epilepsy, and intellectual disability. The encoded protein is responsible for phosphorylation-mediated inactivation of the E1α subunit of branched-chain ketoacid dehydrogenase (BCKDH). Patients with homozygous BCKDK mutations display reductions in BCKDK messenger RNA and protein, E1α phosphorylation, and plasma branched-chain amino acids. Bckdk knockout mice show abnormal brain amino acid profiles and neurobehavioral deficits that respond to dietary supplementation. Thus, autism presenting with intellectual disability and epilepsy caused by BCKDK mutations represents a potentially treatable syndrome.

Published
2012

13. Sequence Variants in SLITRK1 Are Associated with Tourette's Syndrome

Author

Abelson, Jesse F., Kwan, Kenneth Y., O'Roak, Brian J., Baek, Danielle Y., Stillman, Althea A., Morgan, Thomas M., Mathews, Carol A., Pauls, David L., Rašin, Mladen-Roko, Gunel, Murat, Davis, Nicole R., Ercan-Sencicek, A. Gulhan, Guez, Danielle H., Spertus, John A., Leckman, James F., Dure, Leon S., Kurlan, Roger, Singer, Harvey S., Gilbert, Donald L., Farhi, Anita, Louvi, Angeliki, Lifton, Richard P., Šestan, Nenad, and State, Matthew W.

Published
2005

14. Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease

Author

Mishra-Gorur, Ketu, primary, Barak, Tanyeri, additional, Kaulen, Leon D., additional, Henegariu, Octavian, additional, Jin, Sheng Chih, additional, Aguilera, Stephanie Marie, additional, Yalbir, Ezgi, additional, Goles, Gizem, additional, Nishimura, Sayoko, additional, Miyagishima, Danielle, additional, Djenoune, Lydia, additional, Altinok, Selin, additional, Rai, Devendra K., additional, Viviano, Stephen, additional, Prendergast, Andrew, additional, Zerillo, Cynthia, additional, Ozcan, Kent, additional, Baran, Burcin, additional, Sencar, Leman, additional, Goc, Nukte, additional, Yarman, Yanki, additional, Ercan-Sencicek, A. Gulhan, additional, Bilguvar, Kaya, additional, Lifton, Richard P., additional, Moliterno, Jennifer, additional, Louvi, Angeliki, additional, Yuan, Shiaulou, additional, Deniz, Engin, additional, Brueckner, Martina, additional, and Gunel, Murat, additional

Published
2023
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15. Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities

Author

Cali, Elisa, primary, Suri, Mohnish, additional, Scala, Marcello, additional, Ferla, Matteo P., additional, Alavi, Shahryar, additional, Faqeih, Eissa Ali, additional, Bijlsma, Emilia K., additional, Wigby, Kristen M., additional, Baralle, Diana, additional, Mehrjardi, Mohammad Y.V., additional, Schwab, Jennifer, additional, Platzer, Konrad, additional, Steindl, Katharina, additional, Hashem, Mais, additional, Jones, Marilyn, additional, Niyazov, Dmitriy M., additional, Jacober, Jennifer, additional, Littlejohn, Rebecca Okashah, additional, Weis, Denisa, additional, Zadeh, Neda, additional, Rodan, Lance, additional, Goldenberg, Alice, additional, Lecoquierre, François, additional, Dutra-Clarke, Marina, additional, Horvath, Gabriella, additional, Young, Dana, additional, Orenstein, Naama, additional, Bawazeer, Shahad, additional, Vulto-van Silfhout, Anneke T., additional, Herenger, Yvan, additional, Dehghani, Mohammadreza, additional, Seyedhassani, Seyed Mohammad, additional, Bahreini, Amir, additional, Nasab, Mahya E., additional, Ercan-Sencicek, A. Gulhan, additional, Firoozfar, Zahra, additional, Movahedinia, Mojtaba, additional, Efthymiou, Stephanie, additional, Striano, Pasquale, additional, Karimiani, Ehsan Ghayoor, additional, Salpietro, Vincenzo, additional, Taylor, Jenny C., additional, Redman, Melody, additional, Stegmann, Alexander P.A., additional, Laner, Andreas, additional, Abdel-Salam, Ghada, additional, Li, Megan, additional, Bengala, Mario, additional, Müller, Amelie Johanna, additional, Digilio, Maria C., additional, Rauch, Anita, additional, Gunel, Murat, additional, Titheradge, Hannah, additional, Schweitzer, Daniela N., additional, Kraus, Alison, additional, Valenzuela, Irene, additional, McLean, Scott D., additional, Phornphutkul, Chanika, additional, Salih, Mustafa, additional, Begtrup, Amber, additional, Schnur, Rhonda E., additional, Torti, Erin, additional, Haack, Tobias B., additional, Prada, Carlos E., additional, Alkuraya, Fowzan S., additional, Houlden, Henry, additional, and Maroofian, Reza, additional

Published
2023
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17. Clinical, demographic and genetic features of patients with congenital heart disease: A single center experience

Author

KAYMAKCALAN, Hande, YALCINKAYA, Leyla, NIKEREL, Emrah, YALCIN, Yalim, DONG, Weilai, ERCAN SENCICEK, Adife Gulhan, and Yalçınkaya, Leyla

Subjects
Genetics, Medicine, Congenital heart disease,Genetics,Genetic counseling, Tıp, Congenital heart disease, Genetic counseling
Abstract

Objective: We aimed to evaluate the demographic and clinical characteristics of children with congenital heart disease (CHD) in a private pediatric cardiovascular genetics clinic in Istanbul from January 2016 to July 2018 and increase the awareness and emphasize the importance of genetic counseling in CHD. Patients and Methods: One hundred and seventeen patients (50 female, 67 male) from 3 days of age to 25 years of age in 17 months period ( January 2016 to July 2018) were retrospectively analyzed. Data included age, sex, echocardiography results, extracardiac features, genetic test results, consanguinity and any family member with heart disease. Pearson’s chi-squared test with 1 degree of freedom and 5% significance was used for correlations. Results: Consanguinity rate was 23.9%. Most common diagnosis was Tetralogy of Fallot (TOF) followed by atrial septal defect (ASD) and ventricular septal defect (VSD) equally. 30 patients had genetic testing which revealed a diagnosis in 36.6 % of the patients. 6 patients had DiGeorge, one had Renpenning,one had Kabuki syndrome. We had one NODAL, one MYH7 and one MYH6 variant. Conclusion: Genetic testing in CHD has a high diagnostic yield. Genetic counseling can help diagnostic, prognostic, and therapeutic and family planning decision making.

Published
2022

18. Mutation spectrum of congenital heart disease in a consanguineous Turkish population

Author

Dong, Weilai, primary, Kaymakcalan, Hande, additional, Jin, Sheng Chih, additional, Diab, Nicholas S., additional, Tanıdır, Cansaran, additional, Yalcin, Ali Seyfi Yalim, additional, Ercan‐Sencicek, A. Gulhan, additional, Mane, Shrikant, additional, Gunel, Murat, additional, Lifton, Richard P., additional, Bilguvar, Kaya, additional, and Brueckner, Martina, additional

Published
2022
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20. Prevalence and clinical/molecular characteristics of PTEN mutations in Turkish children with autism spectrum disorders and macrocephaly

Author

Kaymakcalan, Hande, primary, Kaya, İlyas, additional, Cevher Binici, Nagihan, additional, Nikerel, Emrah, additional, Özbaran, Burcu, additional, Görkem Aksoy, Mehmet, additional, Erbilgin, Seda, additional, Özyurt, Gonca, additional, Jahan, Noor, additional, Çelik, Didem, additional, Yararbaş, Kanay, additional, Yalçınkaya, Leyla, additional, Köse, Sezen, additional, Durak, Sibel, additional, and Ercan‐Sencicek, Adife Gulhan, additional

Published
2021
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22. Engineering spatial-organized cardiac organoids for developmental toxicity testing

Author

Hoang, Plansky, primary, Kowalczewski, Andrew, additional, Sun, Shiyang, additional, Winston, Tackla S., additional, Archilla, Adriana M., additional, Lemus, Stephanie M., additional, Ercan-Sencicek, A. Gulhan, additional, Gupta, Abha R., additional, Liu, Wenzhong, additional, Kontaridis, Maria I., additional, Amack, Jeffrey D., additional, and Ma, Zhen, additional

Published
2021
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23. De novo mutations revealed by whole-exome sequencing are strongly associated with autism

Author

Sanders, Stephan J., Murtha, Michael T., Gupta, Abha R., Murdoch, John D., Raubeson, Melanie J., Willsey, A. Jeremy, Ercan-Sencicek, A. Gulhan, DiLullo, Nicholas M., Parikshak, Neelroop N., Stein, Jason L., Walker, Michael F., Ober, Gordon T., Teran, Nicole A., Song, Youeun, El-Fishawy, Paul, Murtha, Ryan C., Choi, Murim, Overton, John D., Bjornson, Robert D., Carriero, Nicholas J., Meyer, Kyle A., Bilguvar, Kaya, Mane, Shrikant M., Sestan, Nenad, Lifton, Richard P., Gunel, Murat, Roeder, Kathryn, Geschwind, Daniel H., Devlin, Bernie, and State, Matthew W.

Subjects
Gene mutations -- Health aspects, Single nucleotide polymorphisms -- Research, Autism -- Genetic aspects -- Risk factors -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Multiple studies have confirmed the contribution of rare de novo copy number variations to the risk for autism spectrum disorders (1-3). But whereas denovo single nucleotide variants have been identified in affected individuals (4), their contribution to risk has yet to be clarified. Specifically, the frequency and distribution of these mutations have not been well characterized in matched unaffected controls, and such data are vital to the interpretation of de novo coding mutations observed in probands. Here we show, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects. On the basis of mutation rates in unaffected individuals, we demonstrate that multiple independent denovosingle nucleotide variants in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there is a single instance in probands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (sodium channel, voltage-gated, type II, a subunit), a result that is highly unlikely by chance., We completed whole-exome sequencing in 238 families from the Simons Simplex Collection (SSC), a comprehensively phenotyped autism spectrum disorders (ASD) cohort consisting of pedigrees with two unaffected parents, an affected [...]

Published
2012
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24. L-histidine decarboxylase and Tourette's syndrome

Author

Ercan-Sencicek, A. Gulhan, Stillman, Althea A., Ghosh, Ananda K., Bilguvar, Kaya, O'Roak, Brian J., Mason, Christopher E., Abbott, Thomas, Gupta, Abha, King, Robert A., Pauls, David L., Tischfield, Jay A., Heiman, Gary A., Singer, Harvey S., Gilbert, Donald L., Hoekstra, Pieter J., Morgan, Thomas M., Loring, Erin, Yasuno, Katsuhito, Fernandez, Thomas, Sanders, Stephan, Louvi, Angeliki, Cho, Judy H., Mane, Shrikant, Colangelo, Christopher M., Biederer, Thomas, Lifton, Richard P., Gunel, Murat, and State, Matthew W.

Subjects
Decarboxylases -- Genetic aspects, Gene mutations -- Analysis, Histidine -- Research, Tourette's syndrome -- Genetic aspects, Tourette's syndrome -- Diagnosis, Tourette's syndrome -- Care and treatment
Abstract

An analysis of linkage in a two-generation pedigree leading to the identification of a rare functional mutation in the HDC gene encoding L-histidine decarboxylase and Tourette's syndrome, the rate-limiting enzyme in histamine biosynthesis is described. The study findings along with the published data from model system provide insight into the role for histaminergic neurotransmission in the mechanism and modulation of Tourette's syndrome and tics.

Published
2010

25. Biallelic PRMT7pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities

Author

Cali, Elisa, Suri, Mohnish, Scala, Marcello, Ferla, Matteo P., Alavi, Shahryar, Faqeih, Eissa Ali, Bijlsma, Emilia K., Wigby, Kristen M., Baralle, Diana, Mehrjardi, Mohammad Y.V., Schwab, Jennifer, Platzer, Konrad, Steindl, Katharina, Hashem, Mais, Jones, Marilyn, Niyazov, Dmitriy M., Jacober, Jennifer, Littlejohn, Rebecca Okashah, Weis, Denisa, Zadeh, Neda, Rodan, Lance, Goldenberg, Alice, Lecoquierre, François, Dutra-Clarke, Marina, Horvath, Gabriella, Young, Dana, Orenstein, Naama, Bawazeer, Shahad, Vulto-van Silfhout, Anneke T., Herenger, Yvan, Dehghani, Mohammadreza, Seyedhassani, Seyed Mohammad, Bahreini, Amir, Nasab, Mahya E., Ercan-Sencicek, A. Gulhan, Firoozfar, Zahra, Movahedinia, Mojtaba, Efthymiou, Stephanie, Striano, Pasquale, Karimiani, Ehsan Ghayoor, Salpietro, Vincenzo, Taylor, Jenny C., Redman, Melody, Stegmann, Alexander P.A., Laner, Andreas, Abdel-Salam, Ghada, Li, Megan, Bengala, Mario, Müller, Amelie Johanna, Digilio, Maria C., Rauch, Anita, Gunel, Murat, Titheradge, Hannah, Schweitzer, Daniela N., Kraus, Alison, Valenzuela, Irene, McLean, Scott D., Phornphutkul, Chanika, Salih, Mustafa, Begtrup, Amber, Schnur, Rhonda E., Torti, Erin, Haack, Tobias B., Prada, Carlos E., Alkuraya, Fowzan S., Houlden, Henry, and Maroofian, Reza

Abstract

Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyzes the methylation of arginine residues on several protein substrates. Biallelic pathogenic PRMT7variants have previously been associated with a syndromic neurodevelopmental disorder characterized by short stature, brachydactyly, intellectual developmental disability, and seizures. To our knowledge, no comprehensive study describes the detailed clinical characteristics of this syndrome. Thus, we aim to delineate the phenotypic spectrum of PRMT7-related disorder.

Published
2023
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26. Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders

Author

Bakkaloglu, Betul, O'Roak, Brian J., Louvi, Angeliki, Gupta, Abha R., Abelson, Jesse F., Morgan, Thomas M., Chawarska, Katarzyna, Klin, Ami, Ercan-Sencicek, A. Gulhan, Stillman, Althea A., Tanriover, Gamze, Abrahams, Brett S., Duvall, Jackie A., Robbins, Elissa M., Geshwind, Daniel H., Biederer, Thomas, Gunel, Murat, Lifton, Richard P., and State, Matthew W.

Subjects
Human cytogenetics -- Research, Autistic children -- Genetic aspects, Autistic children -- Research, Amino acid sequence -- Research, Biological sciences
Abstract

A de novo chromosome 7q inversion disrupting Autism susceptibility candidate 2 (AUTS2) and Contactin Associated Protein-Like 2 (CNTNAP2) in a child with congitive and social delay is identified. It is suggested that rare variants contribute to the pathophysiology of autism spectrum disorders (ASD).

Published
2008

27. Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE

Author

Celestino-Soper, Patricia B.S., Shaw, Chad A., Sanders, Stephan J., Li, Jian, Murtha, Michael T., Ercan-Sencicek, A. Gulhan, Davis, Lea, Thomson, Susanne, Gambin, Tomasz, Chinault, A. Craig, Ou, Zhishuo, German, Jennifer R., Milosavljevic, Aleksandar, Sutcliffe, James S., Cook, Edwin H., Jr., Stankiewicz, Pawel, State, Matthew W., and Beaudet, Arthur L.

Published
2011
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28. Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases

Author

Perenthaler, Elena, primary, Nikoncuk, Anita, additional, Yousefi, Soheil, additional, Berdowski, Woutje M., additional, Alsagob, Maysoon, additional, Capo, Ivan, additional, van der Linde, Herma C., additional, van den Berg, Paul, additional, Jacobs, Edwin H., additional, Putar, Darija, additional, Ghazvini, Mehrnaz, additional, Aronica, Eleonora, additional, van IJcken, Wilfred F. J., additional, de Valk, Walter G., additional, Medici-van den Herik, Evita, additional, van Slegtenhorst, Marjon, additional, Brick, Lauren, additional, Kozenko, Mariya, additional, Kohler, Jennefer N., additional, Bernstein, Jonathan A., additional, Monaghan, Kristin G., additional, Begtrup, Amber, additional, Torene, Rebecca, additional, Al Futaisi, Amna, additional, Al Murshedi, Fathiya, additional, Mani, Renjith, additional, Al Azri, Faisal, additional, Kamsteeg, Erik-Jan, additional, Mojarrad, Majid, additional, Eslahi, Atieh, additional, Khazaei, Zaynab, additional, Darmiyan, Fateme Massinaei, additional, Doosti, Mohammad, additional, Karimiani, Ehsan Ghayoor, additional, Vandrovcova, Jana, additional, Zafar, Faisal, additional, Rana, Nuzhat, additional, Kandaswamy, Krishna K., additional, Hertecant, Jozef, additional, Bauer, Peter, additional, AlMuhaizea, Mohammed A., additional, Salih, Mustafa A., additional, Aldosary, Mazhor, additional, Almass, Rawan, additional, Al-Quait, Laila, additional, Qubbaj, Wafa, additional, Coskun, Serdar, additional, Alahmadi, Khaled O., additional, Hamad, Muddathir H. A., additional, Alwadaee, Salem, additional, Awartani, Khalid, additional, Dababo, Anas M., additional, Almohanna, Futwan, additional, Colak, Dilek, additional, Dehghani, Mohammadreza, additional, Mehrjardi, Mohammad Yahya Vahidi, additional, Gunel, Murat, additional, Ercan-Sencicek, A. Gulhan, additional, Passi, Gouri Rao, additional, Cheema, Huma Arshad, additional, Efthymiou, Stephanie, additional, Houlden, Henry, additional, Bertoli-Avella, Aida M., additional, Brooks, Alice S., additional, Retterer, Kyle, additional, Maroofian, Reza, additional, Kaya, Namik, additional, van Ham, Tjakko J., additional, and Barakat, Tahsin Stefan, additional

Published
2019
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30. 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, Richard J.L., Ripke, Stephan, Anttila, Verneri, Grove, Jakob, Holmans, Peter, Huang, Hailiang, Klei, Lambertus, Lee, Phil H., Medland, Sarah E., Neale, Benjamin, Robinson, Elise, Weiss, Lauren A., Zwaigenbaum, Lonnie, Yu, Timothy W., Wittemeyer, Kerstin, Willsey, A. Jeremy, Wijsman, Ellen M., Werge, Thomas, Wassink, Thomas H., Waltes, Regina, Walsh, Christopher A., Wallace, Simon, Vorstman, Jacob A.S., Vieland, Veronica J., Vicente, Astrid M., Vanengeland, Herman, Tsang, Kathryn, Thompson, Ann P., Szatmari, Peter, Svantesson, Oscar, Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, State, Matthew W., Soorya, Latha, Silagadze, Teimuraz, Scherer, Stephen W., Schellenberg, Gerard D., Sandin, Sven, Sanders, Stephan J., Saemundsen, Evald, Rouleau, Guy A., Rogé, Bernadette, Roeder, Kathryn, Roberts, Wendy, Reichert, Jennifer, Reichenberg, Abraham, Rehnström, Karola, Regan, Regina, Poustka, Fritz, Poultney, Christopher S., Piven, Joseph, Pinto, Dalila, Pericak-Vance, Margaret A., Pejovic-Milovancevic, Milica, Pedersen, Marianne Giørtz, Pedersen, Carsten Bøcker, Paterson, Andrew D., Parr, Jeremy R., Pagnamenta, Alistair T., Oliveira, Guiomar, Nurnberger, John I., Nordentoft, Merete, Murtha, Michael T., Mouga, Susana, Mortensen, Preben Bo, Mors, Ole, Morrow, Eric M., Moreno-De-Luca, Daniel, Monaco, Anthony P., Minshew, Nancy, Merikangas, Alison, McMahon, William M., McGrew, Susan G., Mattheisen, Manuel, Martsenkovsky, Igor, Martin, Donna M., Mane, Shrikant M., Magnusson, Pall, Magalhaes, Tiago, Maestrini, Elena, Lowe, Jennifer K., Lord, Catherine, Levitt, Pat, Martin, Christa Lese, Ledbetter, David H., Leboyer, Marion, Lecouteur, Ann S., Ladd-Acosta, Christine, Kolevzon, Alexander, Klauck, Sabine M., Jacob, Suma, Iliadou, Bozenna, Hultman, Christina M., Hougaard, David M., Hertz-Picciotto, Irva, Hendren, Robert, Hansen, Christine Søholm, Haines, Jonathan L., Guter, Stephen J., Grice, Dorothy E., Green, Jonathan M., Green, Andrew, Goldberg, Arthur P., Gillberg, Christopher, Gilbert, John, Gallagher, Louise, Freitag, Christine M., Fombonne, Eric, Folstein, Susan E., Fernandez, Bridget, Fallin, M. Daniele, Ercan-Sencicek, A. Gulhan, Ennis, Sean, Duque, Frederico, Duketis, Eftichia, Delorme, Richard, Derubeis, Silvia, Dejonge, Maretha V., Dawson, Geraldine, Cuccaro, Michael L., Correia, Catarina T., Conroy, Judith, Conceição, Ines C., Chiocchetti, Andreas G., Celestino-Soper, Patrícia B.S., Casey, Jillian, Cantor, Rita M., Café, Cátia, Bybjerg-Grauholm, Jonas, Brennan, Sean, Bourgeron, Thomas, Bolton, Patrick F., Bölte, Sven, Bolshakova, Nadia, Betancur, Catalina, Bernier, Raphael, Beaudet, Arthur L., Battaglia, Agatino, Bal, Vanessa H., Baird, Gillian, Bailey, Anthony J., Bækvad-Hansen, Marie, Bader, Joel S., Bacchelli, Elena, Anagnostou, Evdokia, Amaral, David, Almeida, Joana, Børglum, Anders D., Buxbaum, Joseph D., Chakravarti, Aravinda, Cook, Edwin H., Coon, Hilary, Geschwind, Daniel H., Gill, Michael, Hakonarson, Hakon, Hallmayer, Joachim, Palotie, Aarno, Santangelo, Susan, Sutcliffe, James S., Arking, Dan E., Devlin, Bernie, Daly, Mark J., Anney, Richard J.L., Ripke, Stephan, Anttila, Verneri, Grove, Jakob, Holmans, Peter, Huang, Hailiang, Klei, Lambertus, Lee, Phil H., Medland, Sarah E., Neale, Benjamin, Robinson, Elise, Weiss, Lauren A., Zwaigenbaum, Lonnie, Yu, Timothy W., Wittemeyer, Kerstin, Willsey, A. Jeremy, Wijsman, Ellen M., Werge, Thomas, Wassink, Thomas H., Waltes, Regina, Walsh, Christopher A., Wallace, Simon, Vorstman, Jacob A.S., Vieland, Veronica J., Vicente, Astrid M., Vanengeland, Herman, Tsang, Kathryn, Thompson, Ann P., Szatmari, Peter, Svantesson, Oscar, Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, State, Matthew W., Soorya, Latha, Silagadze, Teimuraz, Scherer, Stephen W., Schellenberg, Gerard D., Sandin, Sven, Sanders, Stephan J., Saemundsen, Evald, Rouleau, Guy A., Rogé, Bernadette, Roeder, Kathryn, Roberts, Wendy, Reichert, Jennifer, Reichenberg, Abraham, Rehnström, Karola, Regan, Regina, Poustka, Fritz, Poultney, Christopher S., Piven, Joseph, Pinto, Dalila, Pericak-Vance, Margaret A., Pejovic-Milovancevic, Milica, Pedersen, Marianne Giørtz, Pedersen, Carsten Bøcker, Paterson, Andrew D., Parr, Jeremy R., Pagnamenta, Alistair T., Oliveira, Guiomar, Nurnberger, John I., Nordentoft, Merete, Murtha, Michael T., Mouga, Susana, Mortensen, Preben Bo, Mors, Ole, Morrow, Eric M., Moreno-De-Luca, Daniel, Monaco, Anthony P., Minshew, Nancy, Merikangas, Alison, McMahon, William M., McGrew, Susan G., Mattheisen, Manuel, Martsenkovsky, Igor, Martin, Donna M., Mane, Shrikant M., Magnusson, Pall, Magalhaes, Tiago, Maestrini, Elena, Lowe, Jennifer K., Lord, Catherine, Levitt, Pat, Martin, Christa Lese, Ledbetter, David H., Leboyer, Marion, Lecouteur, Ann S., Ladd-Acosta, Christine, Kolevzon, Alexander, Klauck, Sabine M., Jacob, Suma, Iliadou, Bozenna, Hultman, Christina M., Hougaard, David M., Hertz-Picciotto, Irva, Hendren, Robert, Hansen, Christine Søholm, Haines, Jonathan L., Guter, Stephen J., Grice, Dorothy E., Green, Jonathan M., Green, Andrew, Goldberg, Arthur P., Gillberg, Christopher, Gilbert, John, Gallagher, Louise, Freitag, Christine M., Fombonne, Eric, Folstein, Susan E., Fernandez, Bridget, Fallin, M. Daniele, Ercan-Sencicek, A. Gulhan, Ennis, Sean, Duque, Frederico, Duketis, Eftichia, Delorme, Richard, Derubeis, Silvia, Dejonge, Maretha V., Dawson, Geraldine, Cuccaro, Michael L., Correia, Catarina T., Conroy, Judith, Conceição, Ines C., Chiocchetti, Andreas G., Celestino-Soper, Patrícia B.S., Casey, Jillian, Cantor, Rita M., Café, Cátia, Bybjerg-Grauholm, Jonas, Brennan, Sean, Bourgeron, Thomas, Bolton, Patrick F., Bölte, Sven, Bolshakova, Nadia, Betancur, Catalina, Bernier, Raphael, Beaudet, Arthur L., Battaglia, Agatino, Bal, Vanessa H., Baird, Gillian, Bailey, Anthony J., Bækvad-Hansen, Marie, Bader, Joel S., Bacchelli, Elena, Anagnostou, Evdokia, Amaral, David, Almeida, Joana, Børglum, Anders D., Buxbaum, Joseph D., Chakravarti, Aravinda, Cook, Edwin H., Coon, Hilary, Geschwind, Daniel H., Gill, Michael, Hakonarson, Hakon, Hallmayer, Joachim, Palotie, Aarno, Santangelo, Susan, Sutcliffe, James S., Arking, Dan E., Devlin, Bernie, and Daly, Mark J.

Abstract

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) <1.15). Methods: We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls). Results: We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 × 10-6). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23. Conclusions: This study is an important step in the ongoing endeavour to identify the loci whic

Published
2017

31. Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas

Author

Massachusetts Institute of Technology. Department of Biology, Young, Richard A, Clark, Victoria E, Harmancı, Akdes Serin, Bai, Hanwen, Youngblood, Mark W, Lee, Tong Ihn, Baranoski, Jacob F, Ercan-Sencicek, A Gulhan, Abraham, Brian J, Weintraub, Abraham S, Hnisz, Denes, Simon, Matthias, Krischek, Boris, Erson-Omay, E Zeynep, Henegariu, Octavian, Carrión-Grant, Geneive, Mishra-Gorur, Ketu, Durán, Daniel, Goldmann, Johanna E, Schramm, Johannes, Goldbrunner, Roland, Piepmeier, Joseph M, Vortmeyer, Alexander O, Günel, Jennifer Moliterno, Bilgüvar, Kaya, Yasuno, Katsuhito, Günel, Murat, Young, Richard A., Massachusetts Institute of Technology. Department of Biology, Young, Richard A, Clark, Victoria E, Harmancı, Akdes Serin, Bai, Hanwen, Youngblood, Mark W, Lee, Tong Ihn, Baranoski, Jacob F, Ercan-Sencicek, A Gulhan, Abraham, Brian J, Weintraub, Abraham S, Hnisz, Denes, Simon, Matthias, Krischek, Boris, Erson-Omay, E Zeynep, Henegariu, Octavian, Carrión-Grant, Geneive, Mishra-Gorur, Ketu, Durán, Daniel, Goldmann, Johanna E, Schramm, Johannes, Goldbrunner, Roland, Piepmeier, Joseph M, Vortmeyer, Alexander O, Günel, Jennifer Moliterno, Bilgüvar, Kaya, Yasuno, Katsuhito, Günel, Murat, and Young, Richard A.

Abstract

RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations altering this enzyme have not previously been linked to any pathology in humans, which is a testament to its indispensable role in cell biology. On the basis of a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II (ref. 1), hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors show dysregulation of key meningeal identity genes including WNT6 and ZIC1/ZIC4. In addition to mutations in POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA, and SMO4 we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features.

Published
2017

32. PPIL4is essential for brain angiogenesis and implicated in intracranial aneurysms in humans

Author

Barak, Tanyeri, Ristori, Emma, Ercan-Sencicek, A. Gulhan, Miyagishima, Danielle F., Nelson-Williams, Carol, Dong, Weilai, Jin, Sheng Chih, Prendergast, Andrew, Armero, William, Henegariu, Octavian, Erson-Omay, E. Zeynep, Harmancı, Akdes Serin, Guy, Mikhael, Gültekin, Batur, Kilic, Deniz, Rai, Devendra K., Goc, Nükte, Aguilera, Stephanie Marie, Gülez, Burcu, Altinok, Selin, Ozcan, Kent, Yarman, Yanki, Coskun, Süleyman, Sempou, Emily, Deniz, Engin, Hintzen, Jared, Cox, Andrew, Fomchenko, Elena, Jung, Su Woong, Ozturk, Ali Kemal, Louvi, Angeliki, Bilgüvar, Kaya, Connolly, E. Sander, Khokha, Mustafa K., Kahle, Kristopher T., Yasuno, Katsuhito, Lifton, Richard P., Mishra-Gorur, Ketu, Nicoli, Stefania, and Günel, Murat

Abstract

Intracranial aneurysm (IA) rupture leads to subarachnoid hemorrhage, a sudden-onset disease that often causes death or severe disability. Although genome-wide association studies have identified common genetic variants that increase IA risk moderately, the contribution of variants with large effect remains poorly defined. Using whole-exome sequencing, we identified significant enrichment of rare, deleterious mutations in PPIL4, encoding peptidyl-prolyl cis-transisomerase-like 4, in both familial and index IA cases. Ppil4depletion in vertebrate models causes intracerebral hemorrhage, defects in cerebrovascular morphology and impaired Wnt signaling. Wild-type, but not IA-mutant, PPIL4 potentiates Wnt signaling by binding JMJD6, a known angiogenesis regulator and Wnt activator. These findings identify a novel PPIL4-dependent Wnt signaling mechanism involved in brain-specific angiogenesis and maintenance of cerebrovascular integrity and implicate PPIL4gene mutations in the pathogenesis of IA.

Published
2021
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33. Neurogenetic analysis of childhood disintegrative disorder

Author

Gupta, Abha R., primary, Westphal, Alexander, additional, Yang, Daniel Y. J., additional, Sullivan, Catherine A. W., additional, Eilbott, Jeffrey, additional, Zaidi, Samir, additional, Voos, Avery, additional, Vander Wyk, Brent C., additional, Ventola, Pam, additional, Waqar, Zainulabedin, additional, Fernandez, Thomas V., additional, Ercan-Sencicek, A. Gulhan, additional, Walker, Michael F., additional, Choi, Murim, additional, Schneider, Allison, additional, Hedderly, Tammy, additional, Baird, Gillian, additional, Friedman, Hannah, additional, Cordeaux, Cara, additional, Ristow, Alexandra, additional, Shic, Frederick, additional, Volkmar, Fred R., additional, and Pelphrey, Kevin A., additional

Published
2017
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34. Integrated genomic characterization of IDH1-mutant glioma malignant progression

Author

Bai, Hanwen, Harmanci, Akdes Serin, Erson-Omay, E. Zeynep, Li, Jie, Coskun, Sueleyman, Simon, Matthias, Krischek, Boris, Ozduman, Koray, Omay, S. Buelent, Sorensen, Eric A., Turcan, Sevin, Bakirciglu, Mehmet, Carrion-Grant, Geneive, Murray, Phillip B., Clark, Victoria E., Ercan-Sencicek, A. Gulhan, Knight, James, Sencar, Leman, Altinok, Selin, Kaulen, Leon D., Guelez, Burcu, Timmer, Marco, Schramm, Johannes, Mishra-Gorur, Ketu, Henegariu, Octavian, Moliterno, Jennifer, Louvi, Angeliki, Chan, Timothy A., Tannheimer, Stacey L., Pamir, M. Necmettin, Vortmeyer, Alexander O., Bilguvar, Kaya, Yasuno, Katsuhito, Guenel, Murat, Bai, Hanwen, Harmanci, Akdes Serin, Erson-Omay, E. Zeynep, Li, Jie, Coskun, Sueleyman, Simon, Matthias, Krischek, Boris, Ozduman, Koray, Omay, S. Buelent, Sorensen, Eric A., Turcan, Sevin, Bakirciglu, Mehmet, Carrion-Grant, Geneive, Murray, Phillip B., Clark, Victoria E., Ercan-Sencicek, A. Gulhan, Knight, James, Sencar, Leman, Altinok, Selin, Kaulen, Leon D., Guelez, Burcu, Timmer, Marco, Schramm, Johannes, Mishra-Gorur, Ketu, Henegariu, Octavian, Moliterno, Jennifer, Louvi, Angeliki, Chan, Timothy A., Tannheimer, Stacey L., Pamir, M. Necmettin, Vortmeyer, Alexander O., Bilguvar, Kaya, Yasuno, Katsuhito, and Guenel, Murat

Abstract

Gliomas represent approximately 30% of all central nervous system tumors and 80% of malignant brain tumors(1). To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate dehydrogenase 1), we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression and DNA methylation profiling, demonstrated nonlinear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways and upregulation of the FOXM1- and E2F2-mediated cell cycle transitions, as well as epigenetic silencing of developmental transcription factor genes bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extraterminal (BET) family as a potential therapeutic approach.

Published
2016

35. Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas

Author

Clarke, Victoria E., Harmanci, Akdes Serin, Bai, Hanwen, Youngblood, Mark W., Lee, Tong Ihn, Baranoski, Jacob F., Ercan-Sencicek, A. Gulhan, Abraham, Brian J., Weintraub, Abraham S., Hnisz, Denes, Simon, Matthias, Krischek, Boris, Erson-Omay, E. Zeynep, Henegariu, Octavian, Carrion-Grant, Geneive, Mishra-Gorur, Ketu, Duran, Daniel, Goldmann, Johanna E., Schramm, Johannes, Goldbrunner, Roland, Piepmeier, Joseph M., Vortmeyer, Alexander O., Gunel, Jennifer Molitemo, Bilguvar, Kaya, Yasuno, Katsuhito, Young, Richard A., Gunel, Murat, Clarke, Victoria E., Harmanci, Akdes Serin, Bai, Hanwen, Youngblood, Mark W., Lee, Tong Ihn, Baranoski, Jacob F., Ercan-Sencicek, A. Gulhan, Abraham, Brian J., Weintraub, Abraham S., Hnisz, Denes, Simon, Matthias, Krischek, Boris, Erson-Omay, E. Zeynep, Henegariu, Octavian, Carrion-Grant, Geneive, Mishra-Gorur, Ketu, Duran, Daniel, Goldmann, Johanna E., Schramm, Johannes, Goldbrunner, Roland, Piepmeier, Joseph M., Vortmeyer, Alexander O., Gunel, Jennifer Molitemo, Bilguvar, Kaya, Yasuno, Katsuhito, Young, Richard A., and Gunel, Murat

Abstract

RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations altering this enzyme have not previously been linked to any pathology in humans, which is a testament to its indispensable role in cell biology. On the basis of a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II (ref. 1), hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors show dysregulation of key meningeal identity genes(2,3), including WNT6 and ZIC1/ZIC4. In addition to mutations in POLR2A, NF2, SMARCB1,TRAF7, KLF4, AKT1, PIK3CA, and SMO4-8, we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features.

Published
2016

36. Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas

Author

Clark, Victoria E, primary, Harmancı, Akdes Serin, additional, Bai, Hanwen, additional, Youngblood, Mark W, additional, Lee, Tong Ihn, additional, Baranoski, Jacob F, additional, Ercan-Sencicek, A Gulhan, additional, Abraham, Brian J, additional, Weintraub, Abraham S, additional, Hnisz, Denes, additional, Simon, Matthias, additional, Krischek, Boris, additional, Erson-Omay, E Zeynep, additional, Henegariu, Octavian, additional, Carrión-Grant, Geneive, additional, Mishra-Gorur, Ketu, additional, Durán, Daniel, additional, Goldmann, Johanna E, additional, Schramm, Johannes, additional, Goldbrunner, Roland, additional, Piepmeier, Joseph M, additional, Vortmeyer, Alexander O, additional, Günel, Jennifer Moliterno, additional, Bilgüvar, Kaya, additional, Yasuno, Katsuhito, additional, Young, Richard A, additional, and Günel, Murat, additional

Published
2016
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37. Integrated genomic characterization of IDH1-mutant glioma malignant progression

Author

Bai, Hanwen, primary, Harmancı, Akdes Serin, additional, Erson-Omay, E Zeynep, additional, Li, Jie, additional, Coşkun, Süleyman, additional, Simon, Matthias, additional, Krischek, Boris, additional, Özduman, Koray, additional, Omay, S Bülent, additional, Sorensen, Eric A, additional, Turcan, Şevin, additional, Bakırcığlu, Mehmet, additional, Carrión-Grant, Geneive, additional, Murray, Phillip B, additional, Clark, Victoria E, additional, Ercan-Sencicek, A Gulhan, additional, Knight, James, additional, Sencar, Leman, additional, Altınok, Selin, additional, Kaulen, Leon D, additional, Gülez, Burcu, additional, Timmer, Marco, additional, Schramm, Johannes, additional, Mishra-Gorur, Ketu, additional, Henegariu, Octavian, additional, Moliterno, Jennifer, additional, Louvi, Angeliki, additional, Chan, Timothy A, additional, Tannheimer, Stacey L, additional, Pamir, M Necmettin, additional, Vortmeyer, Alexander O, additional, Bilguvar, Kaya, additional, Yasuno, Katsuhito, additional, and Günel, Murat, additional

Published
2015
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38. Novel compound heterozygous mutations in <italic>GPT2</italic> linked to microcephaly, and intellectual developmental disability with or without spastic paraplegia.

Author

Kaymakcalan, Hande, Yarman, Yanki, Goc, Nukte, Toy, Fatih, Meral, Cihan, Ercan‐Sencicek, A. Gulhan, and Gunel, Murat

Abstract

We here describe novel compound heterozygous missense variants, NM_133443:c.[400C>T] and NM_133443:[1435G>A], in the glutamic‐pyruvic transaminase 2 (GPT2) gene in a large consanguineous family with two affected siblings diagnosed with microcephaly intellectual disability and developmental delay (IDD). In addition to these clinical phenotypes, the male sibling has spastic paraplegia, and the female sibling has epilepsy. Their four extended family members have IDD and microcephaly. Both of these variants, c.400C>T (p.R134C) and c.1435G>A (p.V479M), reside in the pyridoxal phosphate‐dependent aminotransferase domain. The missense variants affect highly conserved amino acids and are classified to be disease‐causing by meta‐SVM. The candidate variants were not found in the Exome Aggregation Consortium (ExAC) dataset or in dbSNP. Both GPT2 variants have an allele frequency of 0% (0/ ∼ 600) in the whole‐exome sequenced Turkish cohort. Upon Sanger sequencing, we confirmed these mutations in all affected family members and showed that the index patient and his affected sister inherited one mutant allele from each unaffected parent. To the best of our knowledge, this is the first family in which a novel compound heterozygous variant in the GPT2 gene was identified. [ABSTRACT FROM AUTHOR]

Published
2018
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40. Histidine Decarboxylase Deficiency Causes Tourette Syndrome: Parallel Findings in Humans and Mice

Author

Castellan Baldan, Lissandra, primary, Williams, Kyle A., additional, Gallezot, Jean-Dominique, additional, Pogorelov, Vladimir, additional, Rapanelli, Maximiliano, additional, Crowley, Michael, additional, Anderson, George M., additional, Loring, Erin, additional, Gorczyca, Roxanne, additional, Billingslea, Eileen, additional, Wasylink, Suzanne, additional, Panza, Kaitlyn E., additional, Ercan-Sencicek, A. Gulhan, additional, Krusong, Kuakarun, additional, Leventhal, Bennett L., additional, Ohtsu, Hiroshi, additional, Bloch, Michael H., additional, Hughes, Zoë A., additional, Krystal, John H., additional, Mayes, Linda, additional, de Araujo, Ivan, additional, Ding, Yu-Shin, additional, State, Matthew W., additional, and Pittenger, Christopher, additional

Published
2014
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41. Homozygous loss of DIAPH1 is a novel cause of microcephaly in humans

Author

Ercan-Sencicek, A Gulhan, primary, Jambi, Samira, additional, Franjic, Daniel, additional, Nishimura, Sayoko, additional, Li, Mingfeng, additional, El-Fishawy, Paul, additional, Morgan, Thomas M, additional, Sanders, Stephan J, additional, Bilguvar, Kaya, additional, Suri, Mohnish, additional, Johnson, Michele H, additional, Gupta, Abha R, additional, Yuksel, Zafer, additional, Mane, Shrikant, additional, Grigorenko, Elena, additional, Picciotto, Marina, additional, Alberts, Arthur S, additional, Gunel, Murat, additional, Šestan, Nenad, additional, and State, Matthew W, additional

Published
2014
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42. Rare Copy Number Variants in Tourette Syndrome Disrupt Genes in Histaminergic Pathways and Overlap with Autism

Author

Fernandez, Thomas V., primary, Sanders, Stephan J., additional, Yurkiewicz, Ilana R., additional, Ercan-Sencicek, A. Gulhan, additional, Kim, Young-Shin, additional, Fishman, Daniel O., additional, Raubeson, Melanie J., additional, Song, Youeun, additional, Yasuno, Katsuhito, additional, Ho, Winson S.C., additional, Bilguvar, Kaya, additional, Glessner, Joseph, additional, Chu, Su Hee, additional, Leckman, James F., additional, King, Robert A., additional, Gilbert, Donald L., additional, Heiman, Gary A., additional, Tischfield, Jay A., additional, Hoekstra, Pieter J., additional, Devlin, Bernie, additional, Hakonarson, Hakon, additional, Mane, Shrikant M., additional, Günel, Murat, additional, and State, Matthew W., additional

Published
2012
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43. Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism

Author

Sanders, Stephan J., primary, Ercan-Sencicek, A. Gulhan, additional, Hus, Vanessa, additional, Luo, Rui, additional, Murtha, Michael T., additional, Moreno-De-Luca, Daniel, additional, Chu, Su H., additional, Moreau, Michael P., additional, Gupta, Abha R., additional, Thomson, Susanne A., additional, Mason, Christopher E., additional, Bilguvar, Kaya, additional, Celestino-Soper, Patricia B.S., additional, Choi, Murim, additional, Crawford, Emily L., additional, Davis, Lea, additional, Davis Wright, Nicole R., additional, Dhodapkar, Rahul M., additional, DiCola, Michael, additional, DiLullo, Nicholas M., additional, Fernandez, Thomas V., additional, Fielding-Singh, Vikram, additional, Fishman, Daniel O., additional, Frahm, Stephanie, additional, Garagaloyan, Rouben, additional, Goh, Gerald S., additional, Kammela, Sindhuja, additional, Klei, Lambertus, additional, Lowe, Jennifer K., additional, Lund, Sabata C., additional, McGrew, Anna D., additional, Meyer, Kyle A., additional, Moffat, William J., additional, Murdoch, John D., additional, O'Roak, Brian J., additional, Ober, Gordon T., additional, Pottenger, Rebecca S., additional, Raubeson, Melanie J., additional, Song, Youeun, additional, Wang, Qi, additional, Yaspan, Brian L., additional, Yu, Timothy W., additional, Yurkiewicz, Ilana R., additional, Beaudet, Arthur L., additional, Cantor, Rita M., additional, Curland, Martin, additional, Grice, Dorothy E., additional, Günel, Murat, additional, Lifton, Richard P., additional, Mane, Shrikant M., additional, Martin, Donna M., additional, Shaw, Chad A., additional, Sheldon, Michael, additional, Tischfield, Jay A., additional, Walsh, Christopher A., additional, Morrow, Eric M., additional, Ledbetter, David H., additional, Fombonne, Eric, additional, Lord, Catherine, additional, Martin, Christa Lese, additional, Brooks, Andrew I., additional, Sutcliffe, James S., additional, Cook, Edwin H., additional, Geschwind, Daniel, additional, Roeder, Kathryn, additional, Devlin, Bernie, additional, and State, Matthew W., additional

Published
2011
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45. A novel heterozygous deletion within the 3’ region of the PAX6 gene causing isolated aniridia in a large family group

Author

Bayrakli, Fatih, primary, Guney, Ilter, additional, Bayri, Yasar, additional, Ercan-Sencicek, Adife Gulhan, additional, Ceyhan, Dogan, additional, Cankaya, Tufan, additional, Mason, Christopher, additional, Bilguvar, Kaya, additional, Bayrakli, Sengul, additional, Mane, Shrikant M., additional, State, Matthew W., additional, and Gunel, Murat, additional

Published
2009
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46. A novel syndrome of cerebral cavernous malformation and Greig cephalopolysyndactyly

Author

Bilguvar, Kaya, primary, Bydon, Mohamad, additional, Bayrakli, Fatih, additional, Ercan-Sencicek, A. Gulhan, additional, Bayri, Yasar, additional, Mason, Christopher, additional, DiLuna, Michael L., additional, Seashore, Margretta, additional, Bronen, Richard, additional, Lifton, Richard P., additional, State, Matthew, additional, and Gunel, Murat, additional

Published
2007
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47. Rare deleterious mutations of the gene EFR3A in autism spectrum disorders.

Author

Gupta, Abha R., Pirruccello, Michelle, Feng Cheng, Hyo Jung Kang, Fernandez, Thomas V., Baskin, Jeremy M., Murim Choi, Li Liu, Ercan-Sencicek, Adife Gulhan, Murdoch, John D., Klei, Lambertus, Neale, Benjamin M., Franjic, Daniel, Daly, Mark J., Lifton, Richard P., De Camilli, Pietro, Hongyu Zhao, Šestan, Nenad, and State, Matthew W.

Subjects
AUTISM spectrum disorders, GENETIC mutation, PHOSPHOINOSITIDES, NUCLEOTIDE sequencing, SACCHAROMYCES cerevisiae, GENETICS
Abstract

Background Whole-exome sequencing studies in autism spectrum disorder (ASD) have identified de novo mutations in novel candidate genes, including the synaptic gene Eighty-five Requiring 3A (EFR3A). EFR3A is a critical component of a protein complex required for the synthesis of the phosphoinositide PtdIns4P, which has a variety of functions at the neural synapse. We hypothesized that deleterious mutations in EFR3A would be significantly associated with ASD. Methods We conducted a large case/control association study by deep resequencing and analysis of whole-exome data for coding and splice site variants in EFR3A. We determined the potential impact of these variants on protein structure and function by a variety of conservation measures and analysis of the Saccharomyces cerevisiae Efr3 crystal structure. We also analyzed the expression pattern of EFR3A in human brain tissue. Results Rare nonsynonymous mutations in EFR3A were more common among cases (16 / 2,196 = 0.73%) than matched controls (12 / 3,389 = 0.35%) and were statistically more common at conserved nucleotides based on an experiment-wide significance threshold (P = 0.0077, permutation test). Crystal structure analysis revealed that mutations likely to be deleterious were also statistically more common in cases than controls (P = 0.017, Fisher exact test). Furthermore, EFR3A is expressed in cortical neurons, including pyramidal neurons, during human fetal brain development in a pattern consistent with ASD-related genes, and it is strongly co-expressed (P < 2.2 × 10-16, Wilcoxon test) with a module of genes significantly associated with ASD. Conclusions Rare deleterious mutations in EFR3A were found to be associated with ASD using an experiment-wide significance threshold. Synaptic phosphoinositide metabolism was strongly implicated in syndromic forms of ASD. These data for EFR3A strengthen the evidence for the involvement of this pathway in idiopathic autism. [ABSTRACT FROM AUTHOR]

Published
2014
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48. Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders

Author

Arking, Dan E., Devlin, Bernie, Nørgaard-Pedersen, Bent, Nordentoft, Merete, Ercan-Sencicek, A. Gulhan, Amaral, David, Stefansson, Kari, Correia, Catarina T., Cantor, Rita M., Wijsman, Ellen M., Samocha, Kaitlin E., Anttila, Verneri, Duketis, Eftichia, Taylor, Jacob, Rogé, Bernadette, Hallmayer, Joachim, Børglum, Anders D, Hansen, Christine S., Regan, Regina, Pedersen, Carsten B., Conceição, Inês C., Geschwind, Daniel H., Bybjerg-Grauholm, Jonas, Reichenberg, Abraham, Buxbaum, Joseph D., Neale, Benjamin, Fallin, M. Daniele, Weiner, Daniel J., Ledbetter, David H., Anagnostou, Evdokia, Dumont, Ashley, Van Engeland, Herman, Silagadze, Teimuraz, Almeida, Joana, Santangelo, Susan, Sandin, Sven, Hansen, Christine, Rehnström, Karola, Bader, Joel S., Minshew, Nancy, Wittemeyer, Kerstin, Haines, Jonathan L., Vorstman, Jacob A. S., Bishop, Somer, Stevens, Christine, Magalhaes, Tiago, Hakonarson, Hakon, Guter, Stephen J., Skuse, David, Levitt, Pat, Poultney, Christopher S., Walters, Raymond K., Mortensen, Preben Bo, Magnusson, Pall, Grice, Dorothy E., Battaglia, Agatino, Willsey, A Jeremy, Green, Jonathan M., Svantesson, Oscar, Lord, Catherine, Piven, Joseph, Holmans, Peter, Bækvad-Hansen, Marie, Hultman, Christina M., Ladd-Acosta, Christine, Bourgeron, Thomas, DeRubeis, Silvia, Sutcliffe, James S., Robinson, Elise B., Nurnberger, John I., Baird, Gillian, Sanders, Stephan J, Mattheisen, Manuel, Rouleau, Guy A., Celestino-Soper, Patrícia B. S., Zwaigenbaum, Lonnie, Duque, Frederico, Ennis, Sean, Klei, Lambertus, Gill, Michael, McMahon, William M., Wigdor, Emilie M., McGrew, Susan G., Wallace, Simon, Roberts, Wendy, Casey, Jillian, Pejovic-Milovancevic, Milica, Iliadou, Bozenna, Soorya, Latha, Cook, Edwin H., Coon, Hilary, Stefansson, Hreinn, Cuccaro, Michael L., Paterson, Andrew D., Bölte, Sven, Bernier, Raphael, Merikangas, Alison, LeCouteur, Ann S., Poustka, Fritz, Parr, Jeremy R., Yu, Timothy W., Thompson, Ann P., Beaudet, Arthur L., Moran, Jennifer, Pagnamenta, Alistair T., Goldstein, Jacqueline I., DeLuca, Daniel Moreno, Daly, Mark J, Green, Andrew, Weiss, Lauren A., Palotie, Aarno, Folstein, Susan E., Roeder, Kathryn, Smith, George Davey, Jacob, Suma, Mors, Ole, Brennan, Sean, Grove, Jakob, Pinto, Dalila, Bal, Vanessa H., Huang, Hailiang, Waltes, Regina, Cafe, Cátia, Bailey, Anthony J., Delorme, Richard, Reichert, Jennifer, Leboyer, Marion, Walsh, Christopher A., Vicente, Astrid M., Goldberg, Arthur P., Dawson, Geraldine, DeJonge, Maretha V., Mouga, Susana, Hansen, Thomas F., Chiocchetti, Andreas G., Martin, Christa Lese, Scherer, Stephen W., Oliveira, Guiomar, Klauck, Sabine M., Bolton, Patrick F., Pedersen, Marianne G., Gilbert, John, Betancur, Catalina, Okbay, Aysu, Fombonne, Eric, Bolshakova, Nadia, Lowe, Jennifer K., Maestrini, Elena, Pericak-Vance, Margaret A., Martsenkovsky, Igor, Gallagher, Louise, Freitag, Christine M., Werge, Thomas, Vieland, Veronica J., State, Matthew W., Kolevzon, Alexander, Bacchelli, Elena, Poulsen, Jesper, Monaco, Anthony P., Anney, Richard, Howrigan, Daniel, Poterba, Timothy, Mane, Shrikant M., Hougaard, David M, Medland, Sarah E., Chakravarti, Aravinda, Hendren, Robert, Conroy, Judith, Tsang, Kathryn, Gillberg, Christopher, Steinberg, Stacy, Saemundsen, Evald, Fernandez, Bridget, Ripke, Stephan, Murtha, Michael T., Martin, Donna M., Morrow, Eric M., Kosmicki, Jack A., Schellenberg, Gerard D., Lee, Phil H., Wassink, Thomas H., Szatmari, Peter, and Hertz-Picciotto, Irva

Subjects
genetic structures, mental disorders, behavioral disciplines and activities, 3. Good health
Abstract

Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASDs and to identify subgroups of ASD cases, including those with strong acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test, and data from 6,454 families with a child with ASD, we show that polygenic risk for ASDs, schizophrenia, and greater educational attainment is over transmitted to children with ASDs. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strong acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that ASDs’ genetic influences are additive and suggest they create risk through at least partially distinct etiologic pathways.

49. Mutations in BCKD-kinase Lead to a Potentially Treatable Form of Autism with Epilepsy.

Author

Novanno, Gala, El.-Fishawy, Paul, Kayseriti, Hulya, Meguid, Nagwa A., Scott, Eric M., Schroth, Jana, Silhavy, Jennifer L., Kara, Majdi, Khalil, Rehab O., Ben.-Omran, Tawfeg, Ercan.-Sencicek, A. Gulhan, Hashish, Adel F., Sanders, Stephan J., Gupta, Abha R., Hashem, Hebatalla S., Matern, Dietrich, Gabriel, Stacey, Sweetman, Larry, Rahimi, Yasmeen, and Harris, Robert A.

Subjects
*MEDICAL genetics, *AUTISM, *AUTISM spectrum disorders, *SOCIAL interaction, *GENETIC mutation, *PEOPLE with epilepsy, *GENETIC disorders, *RNA, *BRANCHED chain amino acids, *PATIENTS, TREATMENT of developmental disabilities
Abstract

Autism spectrum disorders are a genetically heterogeneous constellation of syndromes characterized by impairments in reciprocal social interaction. Available somatic treatments have limited efficacy. We have identified inactivating mutations in the gene BCKDK (Branched Chain Ketoacid Dehydrogenase Kinase) in consanguineous fatuities with autism, epilepsy, and intellectual disability. The encoded protein is responsible for phosphorylation-mediated inactivation of the E1α subunit of branched-chain ketoacid dehydrogenase (BCKDH). Patients with homozygous BCKDK mutations display reductions in BCKDK messenger RNA and protein, E1α phosphorylation, and plasma branched-chain amino acids. Bckdk knockout mice show abnormal brain amino acid profiles and neurobehavioral deficits that respond to dietary supplementation. Thus, autism presenting with intellectual disability and epilepsy caused by BCKDK mutations represents a potentially treatable syndrome. [ABSTRACT FROM AUTHOR]

Published
2012

50. 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

Geraldine Dawson, Sven Sandin, Frederico Duque, Peter Holmans, Marion Leboyer, Aarno Palotie, Fritz Poustka, Richard Delorme, Stephen Sanders, Alistair T. Pagnamenta, Lonnie Zwaigenbaum, Bridget A. Fernandez, A. Jeremy Willsey, Christine M. Freitag, Christa Lese Martin, Elena Maestrini, Elena Bacchelli, Guiomar Oliveira, Jeremy R. Parr, Guy A. Rouleau, Jonas Bybjerg-Grauholm, Joseph Piven, Latha Soorya, Lauren A. Weiss, Jonathan Green, Carsten Bøcker Pedersen, Louise Gallagher, Regina Regan, Stephan Ripke, Thomas Werge, Pat Levitt, Aravinda Chakravarti, Joana Almeida, Kathryn Roeder, Catalina Betancur, Bernie Devlin, Benjamin M. Neale, Gillian Baird, Jakob Grove, Thomas Bourgeron, David H. Ledbetter, Eftichia Duketis, Karola Rehnström, Gerard D. Schellenberg, Jillian P. Casey, Preben Bo Mortensen, Patrick Bolton, Igor Martsenkovsky, Elise Robinson, Hakon Hakonarson, Vanessa H. Bal, Stacy Steinberg, Christopher Gillberg, Kathryn Tsang, Jacob A. S. Vorstman, Verneri Anttila, Suma Jacob, Judith Conroy, J. Haines, William M. McMahon, Edwin H. Cook, Ann P. Thompson, Inês C. Conceição, Mark J. Daly, Arthur P. Goldberg, Sarah E. Medland, Milica Pejovic-Milovancevic, David M. Hougaard, Shrikant Mane, Christina M. Hultman, Susana Mouga, Hreinn Stefansson, Ellen M. Wijsman, Andreas G. Chiocchetti, Ole Mors, Phil Lee, Richard Anney, Astrid M. Vicente, Veronica J. Vieland, K. Stefansson, Stephen W. Scherer, Teimuraz Silagadze, Pall Magnusson, Donna M. Martin, Merete Nordentoft, Peter Szatmari, Patrícia B. S. Celestino-Soper, Ann S Le-Couteur, Cátia Café, Arthur L. Beaudet, Kerstin Wittemeyer, Anders D. Børglum, Joel S. Bader, Christopher S. Poultney, Hailiang Huang, Alexander Kolevzon, Margaret A. Pericak-Vance, Joachim Hallmayer, Rita M. Cantor, Eric Fombonne, Andrew Green, Dan E. Arking, M. Daniele Fallin, Matthew W. State, Christine Ladd-Acosta, Silvia Derubeis, Raphael Bernier, Regina Waltes, David G. Amaral, Manuel Mattheisen, Abraham Reichenberg, Lambertus Klei, Daniel Moreno-De-Luca, Marie Bækvad-Hansen, Maretha V. Dejonge, Susan G. McGrew, Joseph D. Buxbaum, Hilary Coon, Jennifer Reichert, Michael Gill, Herman Vanengeland, Christine Søholm Hansen, Anthony P. Monaco, Nadia Bolshakova, John I. Nurnberger, Nancy J. Minshew, Michael T. Murtha, Thomas H. Wassink, Evald Saemundsen, Simon Wallace, Sean Brennan, Sean Ennis, A. Gulhan Ercan-Sencicek, Sven Bölte, Oscar Svantesson, Susan L. Santangelo, Andrew D. Paterson, Robert L. Hendren, Timothy W. Yu, Dalila Pinto, D.E. Grice, Alison Merikangas, Stephen J. Guter, Anthony J. Bailey, Bernadette Rogé, Christopher A. Walsh, Susan E. Folstein, Wendy Roberts, Sabine M. Klauck, Marianne Giørtz Pedersen, Tiago R. Magalhaes, John R. Gilbert, Irva Hertz-Picciotto, James S. Sutcliffe, Evdokia Anagnostou, Catarina Correia, Eric M. Morrow, Daniel H. Geschwind, Jennifer K. Lowe, Agatino Battaglia, Bozenna Iliadou, Michael L. Cuccaro, Catherine Lord, MRC Centre for Neuropsychiatric Genetics and Genomics [Cardiff, UK], Cardiff University, The Autism Working Group of the Psychiatric Genomics Consortium was supported by National Institutes of Mental Health (NIMH, USA) grant MH109539, MH094432 and MH094421 to M.J.D. The ACE Network was supported by MH081754 and MH100027 to D.H.G. The Autism Genetic Resource Exchange (AGRE) is a program of Autism Speaks (USA) and was supported by grant MH081810. The Autism Genome Project (AGP) was supported by grants from Autism Speaks, the Canadian Institutes of Health Research (CIHR), Genome Canada, the Health Research Board (Ireland, AUT/ 2006/1, AUT/2006/2, PD/2006/48), the Hilibrand Foundation (USA), the Medical Research Council (UK), the National Institutes of Health (USA, the National Institute of Child Health and Human Development and the National Institute of Mental Health), the Ontario Genomics Institute, and the University of Toronto McLaughlin Centre. The Simons Simplex Collection (SSC) was supported by a grant from the Simons Foundation (SFARI 124827 to the investigators of the Simons Simplex Collection Genetic Consortium), approved researchers can obtain the SSC population dataset described in this study (http://sfari.org/resources/sfari-base) by applying at https://base.sfari.org. The Gene Discovery Project of Johns Hopkins was funded by MH060007, MH081754, and the Simons Foundation. The MonBos Collection study was funded in part through a grant from the Autism Consortium of Boston. Support for the Extreme Discordant Sib-Pair (EDSP) family sample (part of the MonBos collection) was provided by the NLM Family foundation. Support for the Massachusetts General Hospital (MGH)–Finnish collaborative sample was provided by NARSAD. The PAGES collection was funded by NIMH grant MH097849. The collection of data and biomaterials that participated in the NIMH Autism Genetics Initiative has been supported by National Institute of Health grants MH52708, MH39437, MH00219, and MH00980, National Health Medical Research Council grant 0034328, and by grants from the Scottish Rite, the Spunk Fund, Inc., the Rebecca and Solomon Baker Fund, the APEX Foundation, the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD), the endowment fund of the Nancy Pritzker Laboratory (Stanford), and by gifts from the Autism Society of America, the Janet M. Grace Pervasive Developmental Disorders Fund, and families and friends of individuals with autism. The iPSYCH project is funded by The Lundbeck Foundation and the universities and university hospitals of Aarhus and Copenhagen. In addition, the genotyping of iPSYCH samples was supported by grants from the Stanley Foundation, the Simons Foundation (SFARI 311789 to MJD), and NIMH (5U01MH094432-02 to MJD). The Study to Explore Early Development (SEED) was funded by the Centers for Disease Control and Prevention (CDC) grants U10DD000180, U10DD000181, U10DD000182, U10DD000183, U10DD000184, and U10DD000498. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Scientific Organization (NWO 480-05-003), along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. Additional statistical analyses were performed and supported by the Trinity Centre for High Performance Computing (http://www.tchpc.tcd.ie/) funded through Science Foundation Ireland. Computational support for the PAGES collection was provided in part through the computational resources and staff expertise of the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai (https://hpc.mssm.edu). Data QC and statistical analyses of the iPSYCH samples were performed at the high-performance computing cluster GenomeDK (http://genome.au.dk) at the Center for Integrative Sequencing, iSEQ, Aarhus University. iSEQ provided computed time, data storage, and technical support for the study., Richard JL Anney, Email: anneyr@cardiff.ac.uk, Affiliation/s: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, CF24 4HQ, UK, Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Stephan Ripke, Email: ripke@atgu.mgh.harvard.edu, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA, Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, CCM, Berlin 10117, Germany. Verneri Anttila, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Jakob Grove, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, DK-8000, Denmark, Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, DK-8000, Denmark, Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark. Peter Holmans, Affiliation/s: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, CF24 4HQ, UK. Hailiang Huang, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Lambertus Klei, Affiliation/s: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Phil H Lee, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Department of Psychiatry, Harvard Medical School, Boston, MA 02115, USA. Sarah E Medland, Affiliation/s: Queensland Institute of Medical Research Brisbane, QLD, 4006, Australia. Benjamin Neale, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Elise Robinson, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Lauren A Weiss, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA, Inst Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA. Lonnie Zwaigenbaum, Affiliation/s: Department of Pediatrics, University of Alberta, Edmonton, AB, T6G 1C9, Canada. Timothy W Yu, Affiliation/s: Division of Genetics, Children ’ s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA. Kerstin Wittemeyer, Affiliation/s: School of Education, University of Birmingham, Birmingham, B15 2TT, UK. A.Jeremy Willsey, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Ellen M Wijsman, Affiliation/s: Department of Medicine, University of Washington, Seattle, WA 98195, USA, Department of Biostatistics, University of Washington, Seattle, WA 98195, USA. Thomas Werge, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Institute of Biological Psychiatry, MHC Sct Hans, Mental Health Services Copenhagen, Roskilde, Denmark, Department of Clinical Medicine, University of Copenhagen, Copenhagen, DK-2200, Denmark. Thomas H Wassink, Affiliation/s: Department of Psychiatry, Carver College of Medicine, Iowa City, IA 52242, USA. Regina Waltes, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany. Christopher A Walsh, Affiliation/s: Division of Genetics, Children ’ s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA, Program in Genetics and Genomics, Harvard Medical School, Boston, MA 02115, USA, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA, Department of Neurology, Harvard Medical School, Boston, MA 02115, USA, Simon Wallace, Affiliation/s: Department of Psychiatry, University of Oxford and Warneford Hospital, Oxford, OX3 7JX, UK. Jacob AS Vorstman, Affiliation/s: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands. Veronica J Vieland, Affiliation/s: Battelle Center for Mathematical Medicine, The Research Institute at Nationwide Children ’ s Hospital, Columbus, OH 43205, USA. Astrid M Vicente, Affiliation/s: Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, 1600, Portugal, Center for Biodiversity, Functional and Integrative Genomics, Campus da FCUL, Lisboa, 1649, Portugal. Herman vanEngeland, Affiliation/s: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands. Kathryn Tsang, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA, Inst Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA. Ann P Thompson, Affiliation/s: Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, ON, L8S 4L8, Canada. Peter Szatmari, Affiliation/s: Department of Psychiatry, University of Toronto, ON, M5T 1R8, Canada. Oscar Svantesson, Affiliation/s: Karolinska Institutet, Solna, SE-171 77, Sweden. Stacy Steinberg, Affiliation/s: deCODE Genetics, Reykjavik, IS-101, Iceland. Kari Stefansson, Affiliation/s: deCODE Genetics, Reykjavik, IS-101, Iceland. Hreinn Stefansson, Affiliation/s: deCODE Genetics, Reykjavik, IS-101, Iceland. Matthew W State, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Latha Soorya, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Rush University Medical Center, Chicago, IL 60612, USA. Teimuraz Silagadze, Affiliation/s: Department of Psychiatry and Drug Addiction, Tbilisi State Medical University, Tbilisi, 0186, Georgia. Stephen W Scherer, Affiliation/s: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, M5G 1L4, Canada, McLaughlin Centre, University of Toronto, Toronto, ON, M5G 0A4, Canada, Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada. Gerard D Schellenberg, Affiliation/s: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19102, USA. Sven Sandin, Affiliation/s: Karolinska Institutet, Solna, SE-171 77, Sweden. Stephan J Sanders, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Evald Saemundsen, Affiliation/s: State Diagnostic and Counseling Centre, Kopavogur, IS-201, Iceland. Guy A Rouleau, Affiliation/s: Montreal Neurological Institute, Dept of Neurology and Neurosurgery, McGill University, Montreal, QC, H3A 2B4, Canada. Bernadette Rogé, Affiliation/s: Centre d ’ Etudes et de Recherches en Psychopathologie, Toulouse University, Toulouse, 31058, France. Kathryn Roeder, Affiliation/s: Department of Computational Biology, Carnegie Mellon University, Pittsburgh, PA 15213, USA, Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 15213, USA. Wendy Roberts, Affiliation/s: Autism Research Unit, The Hospital for Sick Children, Toronto, ON, M5G 1L4, Canada. Jennifer Reichert, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Abraham Reichenberg, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Karola Rehnström, Affiliation/s: Sanger Institute, Hinxton, CB10 1SA, UK. Regina Regan, Affiliation/s: National Childrens Research Centre, Our Lady ’ s Hospital Crumlin, Dublin, D12, Ireland, Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland. Fritz Poustka, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany. Christopher S Poultney, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Joseph Piven, Affiliation/s: University of North Carolina, Chapel Hill, NC 27599, USA. Dalila Pinto, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Margaret A Pericak-Vance, Affiliation/s: The John P Hussman Institute for Human Genomics, University of Miami, Miami, FL 33101, USA. Milica Pejovic-Milovancevic, Affiliation/s: Institute of Mental Health and Medical Faculty, University of Belgrade, Belgrade, 11 000, Serbia. Marianne Giørtz Pedersen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, National Centre for Register-based Research, Aarhus University, Aarhus, Denmark, Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark. Carsten Bøcker Pedersen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark. Andrew D Paterson, Affiliation/s: Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, M5G 1L4, Canada, Dalla Lana School of Public Health, Toronto, ON, M5T 3M7, Canada. Jeremy R Parr, Affiliation/s: Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK, Institue of Health and Science, Newcastle University, Newcastle Upon Tyne, NE2 4AX, UK. Alistair T Pagnamenta, Affiliation/s: Wellcome Trust Centre for Human Genetics, OxfordUniversity,Oxford,OX37BN,UK. Guiomar Oliveira, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal, University Clinic of Pediatrics and Institute for Biomedical Imaging and Life Science, Faculty of Medicine, University of Coimbra, Coimbra, 3041-80, Portugal. John I Nurnberger, Affiliation/s: Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA, Program in Medical Neuroscience, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Merete Nordentoft, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark. Michael T Murtha, Affiliation/s: Programs on Neurogenetics, Yale University School of Medicine, New Haven, CT 06520, USA. Susana Mouga, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal, University Clinic of Pediatrics and Institute for Biomedical Imaging and Life Science, Faculty of Medicine, University of Coimbra, Coimbra, 3041-80, Portugal. Preben Bo Mortensen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Na- tional Centre for Register-based Research, Aarhus University, Aarhus, Denmark, Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark, Ole Mors, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark. Eric M Morrow, Affiliation/s: Department of Psychiatry and Human Behaviour, Brown University, Providence, RI 02912, USA. Daniel Moreno-De-Luca, Affiliation/s: Department of Psychiatry and Hu- man Behaviour, Brown University, Providence, RI 02912, USA. Anthony P Monaco, Affiliation/s: Wellcome Trust Centre for Human Genetics, Oxford University, Oxford, OX3 7BN, UK, Tufts University, Boston, MA 02155?, USA. Nancy Minshew, Affiliation/s: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Alison Merikangas, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. William M McMahon, Affiliation/s: Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA. Susan G McGrew, Affiliation/s: Department of Pediatrics, Vanderbilt University, Nashville, TN 37232, USA. Manuel Mattheisen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, DK-8000, Denmark. Igor Martsenkovsky, Affiliation/s: Department of Child, Adolescent Psychiatry and Medical-Social Rehabilitation, Ukrainian Research Institute of Social Fo- rensic Psychiatry and Drug Abuse, Kyiv, 04080, Ukraine. Donna M Martin, Affiliation/s: Department of Pediatrics and Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA. Shrikant M Mane, Affiliation/s: Yale Center for Genomic Analysis, Yale University School of Medicine, New Haven, CT 06516, USA. Pall Magnusson, Affiliation/s: Department of Child and Adolescent Psychiatry, National University Hospital, Reykjavik, IS-101, Iceland. Tiago Magalhaes, Affiliation/s: National Childrens Research Centre, Our Lady ’ s Hospital Crumlin, Dublin, D12, Ireland, Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland. Elena Maestrini, Affiliation/s: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy. Jennifer K Lowe, Affiliation/s: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA, Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA, Center for Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Catherine Lord, Affiliation/s: Department of Psychiatry, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA. Pat Levitt, Affiliation/s: Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA. Christa LeseMartin, Affiliation/s: Autism and Developmental Medicine Institute, Geisinger Health System, Danville, PA 17837, USA. David H Ledbetter, Affiliation/s: Chief Scientific Officer, Geisinger Health System, Danville, PA 17837, USA. Marion Leboyer, Affiliation/s: FondaMental Foundation, Créteil, 94000, France, INSERM U955, Paris, 94010, France, Faculté de Médecine, Université Paris Est, Créteil, 94000, France, Department of Psychiatry, Henri Mondor-Albert Chene- vier Hospital, Assistance Publique – Hôpitaux de Paris, Créteil, 94000, France, Ann S LeCouteur, Affiliation/s: Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK, Institue of Health and Science, Newcastle University, Newcastle Upon Tyne, NE2 4AX, UK. Christine Ladd-Acosta, Affiliation/s: Department of Epidemiology, Johns Hop- kins Bloomberg School of Public Health, Baltimore, MD 21205, USA. Alexander Kolevzon, Affiliation/s: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Sabine M Klauck, Affiliation/s: Division of Molecular Genome Analysis and Working Group Cancer Genome Research, Deutsches Krebsforschungszentrum, Heidelberg, D-69120, Germany. Suma Jacob, Affiliation/s: Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA, Institute of Translational Neuroscience and Department of Psychiatry, University of Minnesota, Minneapolis, MN 55454, USA. Bozenna Iliadou, Affiliation/s: Karolinska Institutet, Solna, SE-171 77, Sweden. Christina M Hultman, Affiliation/s: Karolinska Institutet, Solna, SE-171 77, Sweden. David M Hougaard, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK-2300, Denmark. Irva Hertz-Picciotto, Affiliation/s: Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, CA 95616, USA, The MIND Institute, School of Medicine, University of California Davis, Davis, CA 95817, USA. Robert Hendren, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Christine Søholm Hansen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK-2300, Denmark. Jonathan L Haines, Affiliation/s: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Stephen J Guter, Affiliation/s: Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA. Dorothy E Grice, Affiliation/s: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Jonathan M Green, Affiliation/s: Manchester Academic Health Sciences Centre, Manchester, M13 9NT, UK, Institute of Brain, Behaviour, and Mental Health, University of Manchester, Manchester, M13 9PT, UK. Andrew Green, Affiliation/s: Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland, Centre for Medical Genetics, Our Lady ’ s Hospital Crumlin, Dublin, D12, Ireland. Arthur P Goldberg, Affiliation/s: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Christopher Gillberg, Affiliation/s: Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, S-405 30, Sweden. John Gilbert, Affiliation/s: The John P Hussman Institute for Human Genomics, University of Miami, Miami, FL 33101, USA. Louise Gallagher, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Christine M Freitag, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany. Eric Fombonne, Affiliation/s: Department of Psychiatry and Institute for Development and Disability, Oregon Health and Science University, Portland, OR 97239, USA. Susan E Folstein, Affiliation/s: Division of Child and Adolescent Psychiatry, Department of Psychiatry, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. Bridget Fernandez, Affiliation/s: Memorial University of Newfoundland, St John ’ s, NL, A1B 3X9, Canada. M.Daniele Fallin, Affiliation/s: Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. A.Gulhan Ercan-Sencicek, Affiliation/s: Programs on Neurogenetics, Yale Uni- versity School of Medicine, New Haven, CT 06520, USA. Sean Ennis, Affiliation/s: Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland, Centre for Medical Genetics, Our Lady ’ s Hospital Crumlin, Dublin, D12, Ireland. Frederico Duque, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal, University Clinic of Pediatrics and Institute for Biomedical Imaging and Life Science, Faculty of Medicine, University of Coimbra, Coimbra, 3041-80, Portugal. Eftichia Duketis, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany. Richard Delorme, Affiliation/s: FondaMental Foundation, Créteil, 94000, France, Human Genetics and Cognitive Functions Unit, Institut Pasteur, Paris, 75015, France, Centre National de la Recherche Scientifique URA 2182 Institut Pasteur, Paris, 75724, France, Department of Child and Adolescent Psychiatry, Robert Debré Hospital, Assistance Publique – Hôpitaux de Paris, Paris, 75019, France, Silvia DeRubeis, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Maretha V DeJonge, Affiliation/s: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands. Geraldine Dawson, Affiliation/s: Duke Center for Autism and Brain Developments, Duke University School of Medicine, Durham, NC 27705, USA, Duke Institute for Brain Sciences, Duke University School of Medicine, Durham, NC 27708, USA. Michael L Cuccaro, Affiliation/s: The John P Hussman Institute for Human Genomics, University of Miami, Miami, FL 33101, USA. Catarina T Correia, Affiliation/s: Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, 1600, Portugal, Center for Biodiversity, Functional and Integrative Genomics, Campus da FCUL, Lisboa, 1649, Portugal. Judith Conroy, Affiliation/s: Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland, Temple Street Children ’ s University Hospital, Dublin, D1, Ireland. Ines C Conceição, Affiliation/s: Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, 1600, Portugal, Center for Biodiversity, Functional and Integrative Genomics, Campus da FCUL, Lisboa, 1649, Portugal. Andreas G Chiocchetti, Affiliation/s: Depar tment of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goe the University Frankfurt, Frankfurt am Main, 60528, Germany. Patrícia BS Celestino-Soper, Affiliation/s: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indian- apolis, IN 46202, USA. Jillian Casey, Affiliation/s: Temple Street Children ’ s University Hospital, Dublin, D1, Ireland, Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland. Rita M Cantor, Affiliation/s: Department of Psychiatry, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA, Department of Human Genetics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA. Cátia Café, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal. Jonas Bybjerg-Grauholm, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK-2300, Denmark. Sean Brennan, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Thomas Bourgeron, Affiliation/s: FondaMental Foundation, Créteil, 94000, France, University Paris Diderot, Sorbonne Paris Cité, Paris, 75013, France, Patrick F Bolton, Affiliation/s: Institute of Psychiatry, Kings College London, London, SE5 8AF, UK, South London and Maudsley Biomedical Research Centre for Mental Health, London, SE5 8AF, UK. Sven Bölte, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany, Department of Women ’ s and Children ’ s Health, Center of Neurodevelopmental Disorders, Karolinska Institutet, Stockholm, SE- 113 30, Sweden, Child and Adolescent Psychiatry, Center for Psychiatry Re- search, Stockholm County Council, Stockholm, SE-171 77, Sweden. Nadia Bolshakova, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Catalina Betancur, Affiliation/s: INSERM U1130, Paris, 75005, France, CNRS UMR 8246, Paris, 75005, France, Sorbonne Universités, UPMC Univ Paris 6, Neuroscience Paris Seine, Paris, 75005, France. Raphael Bernier, Affiliation/s: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA. Arthur L Beaudet, Affiliation/s: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Agatino Battaglia, Affiliation/s: Stella Maris Institute for Child and Adolescent Neuropsychiatr, Pisa, 56018, Italy. Vanessa H Bal, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Gillian Baird, Affiliation/s: Paediatric Neurodisability, King ’ s Health Partners, Kings College London, London, SE1 7EH, UK. Anthony J Bailey, Affiliation/s: Department of Psychiatry, University of Oxford and Warneford Hospital, Oxford, OX3 7JX, UK, Mental Health and Addictions Research Unit, University of British Colombia, Vancouver, BC, V5Z 4H4, Canada. Marie Bækvad-Hansen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK-2300, Denmark. Joel S Bader, Affiliation/s: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21218, USA. Elena Bacchelli, Affiliation/s: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy. Evdokia Anagnostou, Affiliation/s: Bloorview Research Institute, University of Toronto, Toronto, ON, M4G 1R8, Canada. David Amaral, Affiliation/s: The MIND Institute, School of Medicine, University of California Davis, Davis, CA 95817, USA, Department of Psychiatry, School of Medicine, University of California Davis, Davis, CA 95817, USA, Department of Behavioural Sciences, School of Medicine, University of California Davis, Davis, CA 95817, USA. Joana Almeida, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal. Anders D Børglum, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, DK-8000, Denmark. Joseph D Buxbaum, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Aravinda Chakravarti, Affiliation/s: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21218, USA. Edwin H Cook, Affiliation/s: Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA. Hilary Coon, Affiliation/s: Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA. Daniel H Geschwind, Affiliation/s: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA, Center for Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA, Department of Human Genetics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA, Michael Gill, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Hakon Hakonarson, Affiliation/s: The Center for Applied Genomics and Division of Human Genetics, Children ’ s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA, Dept of Pediatrics, University of Pennsylvania, Philadelphia, PA 19104, USA. Joachim Hallmayer, Affiliation/s: Department of Psychiatry, Stanford University, Stanford, CA 94305, USA. Aarno Palotie, Affiliation/s: Sanger Institute, Hinxton, CB10 1SA, UK., Anney, Richard J. L., Ripke, Stephan, Anttila, Verneri, Grove, Jakob, Holmans, Peter, Huang, Hailiang, Klei, Lambertu, Lee, Phil H., Medland, Sarah E., Neale, Benjamin, Robinson, Elise, Weiss, Lauren A., Zwaigenbaum, Lonnie, Yu, Timothy W., Wittemeyer, Kerstin, Willsey, A. Jeremy, Wijsman, Ellen M., Werge, Thoma, Wassink, Thomas H., Waltes, Regina, Walsh, Christopher A., Wallace, Simon, Vorstman, Jacob A. S., Vieland, Veronica J., Vicente, Astrid M., Vanengeland, Herman, Tsang, Kathryn, Thompson, Ann P., Szatmari, Peter, Svantesson, Oscar, Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, State, Matthew W., Soorya, Latha, Silagadze, Teimuraz, Scherer, Stephen W., Schellenberg, Gerard D., Sandin, Sven, Sanders, Stephan J., Saemundsen, Evald, Rouleau, Guy A., Rogã©, Bernadette, Roeder, Kathryn, Roberts, Wendy, Reichert, Jennifer, Reichenberg, Abraham, Rehnstrã¶m, Karola, Regan, Regina, Poustka, Fritz, Poultney, Christopher S., Piven, Joseph, Pinto, Dalila, Pericak-Vance, Margaret A., Pejovic-Milovancevic, Milica, Pedersen, Marianne Giørtz, Pedersen, Carsten Bøcker, Paterson, Andrew D., Parr, Jeremy R., Pagnamenta, Alistair T., Oliveira, Guiomar, Nurnberger, John I., Nordentoft, Merete, Murtha, Michael T., Mouga, Susana, Mortensen, Preben Bo, Mors, Ole, Morrow, Eric M., Moreno-De-Luca, Daniel, Monaco, Anthony P., Minshew, Nancy, Merikangas, Alison, Mcmahon, William M., Mcgrew, Susan G., Mattheisen, Manuel, Martsenkovsky, Igor, Martin, Donna M., Mane, Shrikant M., Magnusson, Pall, Magalhaes, Tiago, Maestrini, Elena, Lowe, Jennifer K., Lord, Catherine, Levitt, Pat, Martin, Christa Lese, Ledbetter, David H., Leboyer, Marion, Lecouteur, Ann S., Ladd-Acosta, Christine, Kolevzon, Alexander, Klauck, Sabine M., Jacob, Suma, Iliadou, Bozenna, Hultman, Christina M., Hougaard, David M., Hertz-Picciotto, Irva, Hendren, Robert, Hansen, Christine Søholm, Haines, Jonathan L., Guter, Stephen J., Grice, Dorothy E., Green, Jonathan M., Green, Andrew, Goldberg, Arthur P., Gillberg, Christopher, Gilbert, John, Gallagher, Louise, Freitag, Christine M., Fombonne, Eric, Folstein, Susan E., Fernandez, Bridget, Fallin, M. Daniele, Ercan-Sencicek, A. Gulhan, Ennis, Sean, Duque, Frederico, Duketis, Eftichia, Delorme, Richard, Derubeis, Silvia, Dejonge, Maretha V., Dawson, Geraldine, Cuccaro, Michael L., Correia, Catarina T., Conroy, Judith, Conceiã§ã£o, Ines C., Chiocchetti, Andreas G., Celestino-Soper, Patrícia B. S., Casey, Jillian, Cantor, Rita M., Cafã©, Cã¡tia, Bybjerg-Grauholm, Jona, Brennan, Sean, Bourgeron, Thoma, Bolton, Patrick F., Bã¶lte, Sven, Bolshakova, Nadia, Betancur, Catalina, Bernier, Raphael, Beaudet, Arthur L., Battaglia, Agatino, Bal, Vanessa H., Baird, Gillian, Bailey, Anthony J., Bækvad-Hansen, Marie, Bader, Joel S., Bacchelli, Elena, Anagnostou, Evdokia, Amaral, David, Almeida, Joana, Bã¸rglum, Anders D., Buxbaum, Joseph D., Chakravarti, Aravinda, Cook, Edwin H., Coon, Hilary, Geschwind, Daniel H., Gill, Michael, Hallmayer, Joachim, Palotie, Aarno, Santangelo, Susan, Sutcliffe, James S., Arking, Dan E., Devlin, Bernie, Daly, Mark J., Hakonarson, Hakon, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Fondation FondaMental [Créteil], 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), 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), and 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)

Subjects
0301 basic medicine, Male, INTELLECTUAL DISABILITY, Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium, Autism, Neurodevelopment, Gene Expression, Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, lcsh:RC346-429, 0302 clinical medicine, 2.1 Biological and endogenous factors, Pair 10, Copy-number variation, Aetiology, Autism spectrum disorder, Genetics, Adaptor Proteins, Forkhead Transcription Factors, Serious Mental Illness, 3. Good health, Mental Health, Psychiatry and Mental Health, Meta-analysis, Female, Biotechnology, Human, Autismo, Genetic correlation, Intellectual and Developmental Disabilities (IDD), Clinical Sciences, Gene-set analysi, Genomics, Locus (genetics), FOXP1, Biology, Chromosomes, Heritability, 03 medical and health sciences, Plasma Membrane Calcium-Transporting ATPases, Developmental Neuroscience, REVEALS, mental disorders, LINKAGE, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Meta-analysi, GENOME-WIDE ASSOCIATION, COMMON, Genotyping, Molecular Biology, lcsh:Neurology. Diseases of the nervous system, COPY NUMBER VARIATION, Genetic association, Adaptor Proteins, Signal Transducing, Homeodomain Proteins, [SDV.GEN]Life Sciences [q-bio]/Genetics, Chromosomes, Human, Pair 10, Research, Human Genome, Signal Transducing, Neurosciences, Membrane Proteins, medicine.disease, RISK LOCI, R1, Brain Disorders, Repressor Proteins, 030104 developmental biology, Genetic Loci, Case-Control Studies, Perturbações do Desenvolvimento Infantil e Saúde Mental, Schizophrenia, Carrier Proteins, Gene-set analysis, MENTAL-RETARDATION, SCAN, 030217 neurology & neurosurgery, Transcription Factors, Developmental Biology
Abstract

Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium - Collaborators (162): 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, Parr JR, Pagnamenta AT, Oliveira G, Nurnberger JI, Nordentoft M, Murtha MT, Mouga S, Mortensen PB, Mors O, Morrow EM, Moreno-De-Luca D, Monaco AP, Minshew N, Merikangas A, McMahon WM, McGrew SG, Mattheisen M, Martsenkovsky I, Martin DM, Mane SM, Magnusson P, Magalhaes T, Maestrini E, Lowe JK, Lord C, Levitt P, Martin CL, Ledbetter DH, Leboyer M, LeCouteur AS, Ladd-Acosta C, Kolevzon A, Klauck SM, Jacob S, Iliadou B, Hultman CM, Hougaard DM, Hertz-Picciotto I, Hendren R, Hansen CS, Haines JL, Guter SJ, Grice DE, Green JM, Green A, Goldberg AP, Gillberg C, Gilbert J, Gallagher L, Freitag CM, Fombonne E, Folstein SE, Fernandez B, Fallin MD, Ercan-Sencicek AG, Ennis S, Duque F, Duketis E, Delorme R, DeRubeis S, DeJonge MV, Dawson G, Cuccaro ML, Correia CT, Conroy J, Conceição IC, Chiocchetti AG, Celestino-Soper PBS, Casey J, Cantor RM, Café C, Bybjerg-Grauholm J, Brennan S, Bourgeron T, Bolton PF, Bölte S, Bolshakova N, Betancur C, Bernier R, Beaudet AL, Battaglia A, Bal VH, Baird G, Bailey AJ, Bækvad-Hansen M, Bader JS, Bacchelli E, Anagnostou E, Amaral D, Almeida J, Børglum AD, Buxbaum JD, Chakravarti A, Cook EH, Coon H, Geschwind DH, Gill M, Hallmayer J, Palotie A, Santangelo S, Sutcliffe JS, Arking DE, Devlin B, Daly MJ. Astrid M. Vicente .- Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis do INSA. PMS free full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441062/ 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

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