Author: "Lambertus Klei" / Topic: genetics - Searchworks@Jio Institute Digital Library Search Results

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1. Evaluating and improving health equity and fairness of polygenic scores

Author: Tianyu Zhang, Geyu Zhou, Lambertus Klei, Peng Liu, Alexandra Chouldechova, Hongyu Zhao, Kathryn Roeder, Max G’Sell, and Bernie Devlin
Subjects: Genetics, QH426-470
Abstract: Summary: Polygenic scores (PGSs) are quantitative metrics for predicting phenotypic values, such as human height or disease status. Some PGS methods require only summary statistics of a relevant genome-wide association study (GWAS) for their score. One such method is Lassosum, which inherits the model selection advantages of Lasso to select a meaningful subset of the GWAS single-nucleotide polymorphisms as predictors from their association statistics. However, even efficient scores like Lassosum, when derived from European-based GWASs, are poor predictors of phenotype for subjects of non-European ancestry; that is, they have limited portability to other ancestries. To increase the portability of Lassosum, when GWAS information and estimates of linkage disequilibrium are available for both ancestries, we propose Joint-Lassosum (JLS). In the simulation settings we explore, JLS provides more accurate PGSs compared to other methods, especially when measured in terms of fairness. In analyses of UK Biobank data, JLS was computationally more efficient but slightly less accurate than a Bayesian comparator, SDPRX. Like all PGS methods, JLS requires selection of predictors, which are determined by data-driven tuning parameters. We describe a new approach to selecting tuning parameters and note its relevance for model selection for any PGS. We also draw connections to the literature on algorithmic fairness and discuss how JLS can help mitigate fairness-related harms that might result from the use of PGSs in clinical settings. While no PGS method is likely to be universally portable, due to the diversity of human populations and unequal information content of GWASs for different ancestries, JLS is an effective approach for enhancing portability and reducing predictive bias.
Published: 2024
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2. The Genetic Architecture of Obsessive-Compulsive Disorder: Contribution of Liability to OCD From Alleles Across the Frequency Spectrum

Author: Abraham Reichenberg, Nancy L Pedersen, David Mataix-Cols, Matthew W Halvorsen, Bengt Fundín, Lambertus Klei, Cynthia M Bulik, Dorothy E. Grice, Kathryn Roeder, Christian Rück, B. Devlin, James J Crowley, Christina M. Hultman, Joseph D. Buxbaum, Mikael Landén, Sven Sandin, Elles de Schipper, Julia Boberg, Behrang Mahjani, and Manuel Mattheisen
Subjects: Genetics, Multifactorial Inheritance, Obsessive-Compulsive Disorder, Heritability, Biology, behavioral disciplines and activities, Polymorphism, Single Nucleotide, Genetic architecture, Frequency spectrum, Article, Psychiatry and Mental health, Obsessive compulsive, mental disorders, Genetic variation, Humans, Allele, Allele frequency, Alleles, Genome-Wide Association Study
Abstract: Objective: Obsessive-compulsive disorder (OCD) is known to be substantially heritable; however, the contribution of genetic variation across the allele frequency spectrum to this heritability remains uncertain. The authors used two new homogeneous cohorts to estimate the heritability of OCD from inherited genetic variation and contrasted the results with those of previous studies. Methods: The sample consisted of 2,090 Swedish-born individuals diagnosed with OCD and 4,567 control subjects, all genotyped for common genetic variants, specifically >400,000 single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) ≥0.01. Using genotypes of these SNPs to estimate distant familial relationships among individuals, the authors estimated the heritability of OCD, both overall and partitioned according to MAF bins. Results: Narrow-sense heritability of OCD was estimated at 29% (SE54%). The estimate was robust, varying only modestly under different models. Contrary to an earlier study, however, SNPs with MAF between 0.01 and 0.05 accounted for 10% of heritability, and estimated heritability per MAF bin roughly followed expectations based on a simple model for SNP-based heritability. Conclusions: These results indicate that common inherited risk variation (MAF ≥0.01) accounts for most of the heritable variation in OCD. SNPs with lowMAFcontribute meaningfully to the heritability of OCD, and the results are consistent with expectation under the "infinitesimal model" (also referred to as the "polygenic model"), where risk is influenced by a large number of loci across the genome and across MAF bins.
Published: 2023

3. Age dependent association of inbreeding with risk for schizophrenia in Egypt

Author: Salwa Tobar, Ahmed Eissa, Nahed E. Ibrahim, Shawn Wood, Serkan Erdin, Bernie Devlin, Wafaa El-Bahaei, Ahmed R. Ali, Warda Fathi, Hala El-Boraie, Amal Yassein, Ibtihal Ibrahim, Lambertus Klei, Eman Elsheshtawy, Vishwajit L. Nimgaonkar, Alina Maysterchuk, Hanan El Sayed, Lora McClain, Hala Salah, Farha A El-Chennawi, Chowdari Kodavali, Joel Wood, Hader Mansour, and Michael E. Talkowski
Subjects: Adult, Microcephaly, Consanguinity, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Inbreeding, Risk factor, Genotyping, Biological Psychiatry, Exome sequencing, Genetics, Homozygote, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Schizophrenia, Statistical genetics, Egypt, 030217 neurology & neurosurgery
Abstract: Background Self-reported consanguinity is associated with risk for schizophrenia (SZ) in several inbred populations, but estimates using DNA-based coefficients of inbreeding are unavailable. Further, it is not known whether recessively inherited risk mutations can be identified through homozygosity by descent (HBD) mapping. Methods We studied self-reported and DNA-based estimates of inbreeding among Egyptian patients with SZ (n = 421, DSM IV criteria) and adult controls without psychosis (n = 301), who were evaluated using semi-structured diagnostic interview schedules and genotyped using the Illumina Infinium PsychArray. Following quality control checks, coefficients of inbreeding (F) and regions of homozygosity (ROH) were estimated using PLINK software for HBD analysis. Exome sequencing was conducted in selected cases. Results Inbreeding was associated with schizophrenia based on self-reported consanguinity (χ2 = 4.506, 1 df, p = 0.034) and DNA-based estimates for inbreeding (F); the latter with a significant F × age interaction (β = 32.34, p = 0.0047). The association was most notable among patients older than age 40 years. Eleven ROH were over-represented in cases on chromosomes 1, 3, 6, 11, and 14; all but one region is novel for schizophrenia risk. Exome sequencing identified six recessively-acting genes in ROH with loss-of-function variants; one of which causes primary hereditary microcephaly. Conclusions We propose consanguinity as an age-dependent risk factor for SZ in Egypt. HBD mapping is feasible for SZ in adequately powered samples.
Published: 2020

4. Genome-wide association study identifies new locus associated with OCD

Author: Danielle Posthuma, Bernie Devlin, Edna Grünblatt, Ying Wang, Daniele Cusi, Stephan Ruhrmann, Steven A. Rasmussen, Michael S. Breen, Julia Klawohn, Ana Gabriela Hounie, Aline S. Sampaio, Cristina Barlassina, Marta Ribasés, Jackson G. Thorp, Cynthia M. Bulik, Marco A. Grados, Dan J. Stein, Abby Fyer, Vladimir Coric, Martha J. Falkenstein, Stephanie Le Hellard, Behrang Mahjani, Nathaniel McGregor, Homero Vallada, Miguel Casas, Laurent F. Thomas, Janice Krasnow, Abraham Reichenberg, Donald W. Black, Gwyneth Zai, Norbert Kathmann, Manuel Mattheisen, Nicholas G. Martin, Jason W. Krompinger, Josep Antoni Ramos-Quiroga, Judith Becker Nissen, Helga Ask, Damiaan Denys, Carolina Cappi, Euripedes Constantino Miguel, O. Joseph Bienvenu, Bengt T. Fundin, Lisa Osiecki, Karin J. H. Verweij, Paul Sandor, Jeremy Veenstra-VanderWeele, Maureen Mulhern, Sarah E. Medland, David M. Hougaard, Lauren Erdman, Jan Haavik, James L. Kennedy, Christopher P. Walker, Jurjen J. Luykx, Tim B. Bigdeli, Ian M. Hickie, Nienke Vulink, Maurizio Turiel, Peter Falkai, Enda M. Byrne, Valentina Ciullo, Daniel A. Geller, Liang Kung-Yee, Miriam A. Schiele, Lambertus Klei, Götz Berberich, Thomas Werge, Brion S. Maher, Christie L. Burton, Julia M. Sealock, Sandra Meier, Bernadette Cullen, Stephan Ripke, Dorothy E. Grice, Richard Delorme, Ted Reichborn-Kjennerud, Dongmei Yu, Danielle C. Cath, Lili Milani, Abdel Abdellaoui, Andres Metspalu, María Soler Artigas, Maria Conceição do Rosário, Ole Mors, Brian P. Brennan, Barbara E. Stranger, Ann E. Pulver, Nora I. Strom, Joseph D. Buxbaum, Hans J. Grabe, Jens R. Wendland, Michael H. Bloch, Srdjan Djurovic, Raquel Rabionet, Angel Carracedo, Carlos N. Pato, Erika L. Nurmi, Janet L. Sobell, Kevin S. O’Connell, Michael Wagner, David R. Rosenberg, Jonathan R. I. Coleman, Jeremiah M. Scharf, Kerry J. Ressler, Jaakko Kaprio, Edwin H. Cook, Scott L. Rauch, Federica Piras, Merete Nordentoft, Christian Rück, Fabrizio Piras, John-Anker Zwart, Jason A. Elias, Christopher Pittenger, Lea K. Davis, Margaret A. Richter, Evonne McArthur, Bendik S. Winsvold, Yin Yao, James J. Crowley, David L. Pauls, Rosa Bosch, Xavier Estivil, Matthew Halvorsen, Adrian Camarena, Nancy L. Pedersen, Pino Alonso, Eric A. Storch, Bjarne Hansen, Helena Brentani, James T. McCracken, Jan Maerten Smit, Donald Hucks, Alexandra Havdahl, Gerome Breen, Christina M. Hultman, Benjamin M. Neale, Gregory L. Hanna, Mikael Landén, Christine Lochner, Dirk J.A. Smit, Fabio Macciardi, Carol A. Mathews, Nuria Lanzagorta, Laura G. Sloofman, Cristina Rodriguez-Fontenla, Michael A. Jenike, Michele T. Pato, Marion Leboyer, Humberto Nicolini, Anders D. Børglum, Maria Cristina Cavallini, Wei Guo, Benjamin D. Greenberg, Maiken Elvestad Gabrielsen, Magdalena Janecka, Mark A. Riddle, Paul S. Nestadt, Beatriz Camarena, Valsamma Eapen, Susanne Walitza, Jack Samuels, Fernando S. Goes, Nicole C.R. McLaughlin, S. Evelyn Stewart, Jennifer Reichert, Sven Sandin, Gerd Kvale, Katharina Domschke, Ole A. Andreassen, Elles de Schipper, Paul D. Arnold, Kristi Krebs, Zachary Gerring, Teemu Palviainen, Kathleen D. Askland, Alfredo Ramirez, James A. Knowles, Laura Bellodi, Kristen Hagen, Julia Boberg, Thomas V. Fernandez, Gerald Nestadt, John Piacentini, Jakob Grove, Eske M. Derks, Preben Bo Mortensen, Elinor K. Karlsson, Gianfranco Spalletta, David Mataix-Cols, Katharina Bey, and Jonas Bybjerg-Grauholm
Subjects: Genetics, business.industry, Locus (genetics), Genome-wide association study, Single-nucleotide polymorphism, Heritability, behavioral disciplines and activities, humanities, Genetic architecture, Anorexia nervosa (differential diagnoses), mental disorders, medicine, Anxiety, SNP, medicine.symptom, business
Abstract: Obsessive-compulsive disorder (OCD) is a heritable disorder, but no definitive, replicated OCD susceptibility loci have yet been identified by any genome-wide association study (GWAS). Here, we report results from a GWAS in the largest OCD case-control sample (N = 14,140 OCD cases and N = 562,117 controls) to date. We explored the genetic architecture of OCD, including its genetic relationships to other psychiatric and non-psychiatric phenotypes. In the GWAS analysis, we identified one SNP associated with OCD at a genome-wide significant level. Subsequent gene-based analyses identified additional two genes as potentially implicated in OCD pathogenesis. All SNPs combined explained 16% of the heritability of OCD. We show sub-stantial positive genetic correlations between OCD and a range of psychiatric disorders, including anxiety disorders, anorexia nervosa, and major depression. We thus for the first time provide evidence of a genome-wide locus implicated in OCD and strengthen previous literature suggesting a polygenic nature of this disorder.
Published: 2021

5. Prevalence and phenotypic impact of rare potentially damaging variants in autism spectrum disorder

Author: Bernie Devlin, Silvia De Rubeis, Michael E. Talkowski, Kathryn Roeder, Maureen Mulhern, Joseph D. Buxbaum, Christina Gustavsson Mahjani, Behrang Mahjani, Sven Sandin, Christina M. Hultman, Lambertus Klei, Xinyi Xu, Jack Fu, F. Kyle Satterstrom, Dorothy E. Grice, and Abraham Reichenberg
Subjects: DNA Copy Number Variations, Autism Spectrum Disorder, Population, Intellectual disability, Transposases, Copy number variant, PAGES, Developmental Neuroscience, Prevalence, Humans, Medicine, Copy-number variation, Autistic Disorder, RC346-429, education, Molecular Biology, Exome sequencing, Genetics, education.field_of_study, business.industry, Research, Whole exome sequencing, Matrix Attachment Region Binding Proteins, medicine.disease, Human genetics, Single nucleotide variant, Psychiatry and Mental health, Phenotype, Autism spectrum disorder, Cohort, Autism, Neurology. Diseases of the nervous system, business, Developmental Biology
Abstract: Background The Autism Sequencing Consortium identified 102 high-confidence autism spectrum disorder (ASD) genes, showing that individuals with ASD and with potentially damaging single nucleotide variation (pdSNV) in these genes had lower cognitive levels and delayed age at walking, when compared to ASD participants without pdSNV. Here, we made use of a Swedish sample of individuals with ASD (called PAGES, for Population-Based Autism Genetics & Environment Study) to evaluate the frequency of pdSNV and their impact on medical and psychiatric phenotypes, using an epidemiological frame and universal health reporting. We then combine findings with those for potentially damaging copy number variation (pdCNV). Methods SNV and CNV calls were generated from whole-exome sequencing and chromosome microarray data, respectively. Birth and medical register data were used to collect phenotypes. Results Of 808 individuals assessed by sequencing, 69 (9%) had pdSNV in the 102 ASC genes, and 144 (18%) had pdSNV in the 102 ASC genes or in a larger set of curated neurodevelopmental genes (from the Deciphering Developmental Disorders study, the gene2phenotype database, and the Radboud University gene lists). Three or more individuals had pdSNV in GRIN2B, POGZ, SATB1, DYNC1H1, SCN8A, or CREBBP. In comparison, out of the 996 individuals from whom CNV were called, 105 (11%) carried one or more pdCNV, including four or more individuals with CNV in the recurrent 15q11q13, 22q11.2, and 16p11.2 loci. Carriers of pdSNV were more likely to have intellectual disability (ID) and epilepsy, while carriers of pdCNV showed increased rates of congenital anomalies and scholastic skill disorders. Carriers of either pdSNV or pdCNV were more likely to have ID, scholastic skill disorders, and epilepsy. Limitations The cohort only included individuals with autistic disorder, the more severe form of ASD, and phenotypes are defined from medical registers. Not all genes studied are definitively ASD genes, and we did not have de novo information to aid in classification. Conclusions In this epidemiological sample, rare pdSNV were more common than pdCNV and the combined yield of potentially damaging variation was substantial at 27%. The results provide compelling rationale for the use of high-throughout sequencing as part of routine clinical workup for ASD and support the development of precision medicine in ASD.
Published: 2021

6. The genetic architecture of obsessive-compulsive disorder: alleles across the frequency spectrum contribute liability to OCD

Author: Behrang Mahjani, Kathryn Roeder, Christina M. Hultman, David Mataix-Cols, Bernie Devlin, Christian Rück, Manuel Mattheisen, E. de Schipper, D.E. Grice, Julia Boberg, Matthew Halvorsen, Nancy L. Pedersen, Bengt T. Fundin, James J. Crowley, Cynthia M. Bulik, Joseph D. Buxbaum, Sven Sandin, Lambertus Klei, Mikael Landén, and Avi Reichenberg
Subjects: Minor allele frequency, Genetics, Genetic variation, Genotype, Single-nucleotide polymorphism, Heritability, Biology, Allele, Allele frequency, Genetic architecture
Abstract: ObjectiveObsessive-compulsive disorder (OCD) is known to be substantially heritable; however, the contribution of common genetic variation across the allele frequency spectrum to this heritability remains uncertain. We use two new, homogenous cohorts to estimate heritability of OCD from common genetic variation and contrast results with prior studies.MethodsThe sample consisted of 2096 Swedish-born individuals diagnosed with OCD and 4609 controls, all genotyped for common genetic variants, specifically >400,000 single nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) ≥ 0.01. Using genotypes of these SNPs to estimate distant familial relationships among individuals, we estimated heritability of OCD, both overall and partitioned according to MAF bins.ResultsWe estimated narrow-sense heritability of 28% (SE=4%). The estimate was robust, varying only modestly under different models. Contrary to an earlier study, however, SNPs with MAF between 0.01 and 0.05 accounted for 8% of heritability and estimated heritability per bin roughly follows expectations based on a simple model for SNP-based heritability.ConclusionsThese results indicate that common inherited risk variation (MAF ≥ 0.01) accounts for most of the heritable variation in OCD. SNPs with low MAF contribute meaningfully to the heritability of OCD and the results are consistent with expectation under the “infinitesimal model,” where risk is influenced by a large number of loci across the genome and across MAF bins.
Published: 2021

7. Prevalence and Phenotypic Impact of Rare Likely Pathogenic Variants in Autism Spectrum Disorder

Author: Sven Sandin, Bernie Devlin, Silvia De Rubeis, Kathryn Roeder, Behrang Mahjani, Christina Gustavsson Mahjani, A. Reichenberg, Michael E. Talkowski, Satterstrom Fk, Maureen Mulhern, D.E. Grice, Lambertus Klei, Jack Fu, Christina M. Hultman, Joseph D. Buxbaum, and Xu X
Subjects: Genetics, Autism spectrum disorder, mental disorders, medicine, Biology, medicine.disease, Phenotype, Likely pathogenic
Abstract: Background: Copy number variants (CNVs) and single nucleotide variants (SNVs) are sources of risk for autism spectrum disorder (ASD). The distribution of such pathogenic variants in individuals with ASD and the characterization of those who carry such variants versus those who do not are understudied at the population level. We describe a population sample from Sweden, evaluating the distribution of likely pathogenic variants and their impact on medical, neurological, and psychiatric phenotypes.Methods: The genotyped sample consisted of 1,236 children born in Sweden with autistic disorder, a severe form of ASD (International Classification of Diseases, Tenth Revision, code F84.0.) Of these individuals, CNVs were called from 997, while SNVs were called from 808. Results: Out of 997 individuals from whom CNVs were called, 104 (10.4 %) carried one or more likely pathogenic CNV, including 15q11q13 (n=8), 15q13.3 (n=5), 16p13.11 (n=5), 16p11.11 (n=5), 22q11.2 (n=5). Of 808 individuals assessed by whole-exome sequencing, 69 (8.5%) had a likely pathogenic SNV, including in GRIN2B (n = 6), POGZ (n = 5), SATB1 (n=4), DYNC1H1 (n=4), and CREBBP (n=3). Fourteen individuals carried two likely pathogenic CNVs, and 5 carried a likely pathogenic CNV and SNV. Carriers of likely pathogenic CNVs or SNVs were more likely to have intellectual disability (ID), scholastic skill disorders, and epilepsy, with odds ratios of 2.31 (95%CI, 1.55,3.47), 1.98 (95%CI, 1.19,3.21), and 1.63 (95%CI, 1.08,2.44) respectively. Carriers of likely pathogenic CNVs also showed significant increased rates of congenital anomalies. We compared rates of likely pathogenic CNVs, SNVs, and phenotypes from genotyped AD subjects with and without ID: rates were not significantly different between groups. Limitations: As a case-control cohort, we did not have de novo information to aid in classification. More broadly, there were judgment calls involved in identifying likely pathogenic variants. For these reasons, some misclassification is possible. In addition, phenotypes are defined from medical registers, which may lead to underestimates of milder findings.Conclusions: People with ASD who carry likely pathogenic CNVs or SNVs show increased rates of various comorbidities, most prominently ID. Despite the strong association with ID, conditioning on its presence explains little of the variation for other comorbidities and physical traits.
Published: 2020

8. Genome-Wide Association Identifies the First Risk Loci for Psychosis in Alzheimer Disease

Author: Sverre Bergh, Ingvild Saltvedt, Elise A. Weamer, Bernie Devlin, Arvid Rongve, Srdjan Djurovic, Patrizia Mecocci, Clive Ballard, Dag Aarsland, Oscar L. Lopez, Sonia Moreno-Grau, Janet C Harwood, Rebecca Sims, Geir Selbæk, Barbara Borroni, Davide Seripa, Diana De Ronchi, Robert A. Sweet, Gianluigi Forloni, Julie Williams, Ole A. Andreassen, Eystein Stordal, Isabel Hernández, Alessandro Serretti, Lavinia Athanasiu, Mercè Boada, Bo Engdahl, Lambertus Klei, Sergi Valero, Basavaraj Hooli, M. Ilyas Kamboh, Mary Ann A. DeMichele-Sweet, Antonis Politis, Agustín Ruiz, Lora McClain, Tatiana Foroud, Byron Creese, Peter Holmans, Richard Mayeux, Håvard K. Skjellegrind, Diego Albani, Lluís Tárraga, Yushi Liu, Emilio Alarcón-Martín, DeMichele-Sweet M.A.A., Klei L., Creese B., Harwood J.C., Weamer E.A., McClain L., Sims R., Hernandez I., Moreno-Grau S., Tarraga L., Boada M., Alarcon-Martin E., Valero S., Liu Y., Hooli B., Aarsland D., Selbaek G., Bergh S., Rongve A., Saltvedt I., Skjellegrind H.K., Engdahl B., Stordal E., Andreassen O.A., Djurovic S., Athanasiu L., Seripa D., Borroni B., Albani D., Forloni G., Mecocci P., Serretti A., De Ronchi D., Politis A., Williams J., Mayeux R., Foroud T., Ruiz A., Ballard C., Holmans P., Lopez O.L., Kamboh M.I., Devlin B., and Sweet R.A.
Subjects: 0301 basic medicine, Psychosis, Hallucinations, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Genetic correlation, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Alzheimer Disease, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Oxidoreductases Acting on Sulfur Group Donors, Bipolar disorder, Molecular Biology, Genetics, business.industry, ad, medicine.disease, Genetic architecture, Psychiatry and Mental health, 030104 developmental biology, Psychotic Disorders, Schizophrenia, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD+P). AD+P affects ∼50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD-P). Although the estimated heritability of AD+P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5,445 AD+P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p=1.26×10−8) and one spanning the 3’-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p=3.24×10−8), had genome-wide significant associations with AD+P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD+P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD+P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.
Published: 2020
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9. Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism

Author: Gail E. Herman, Jennifer Reichert, Camilla Stoltenberg, Stephen Sanders, Menachem Fromer, Branko Aleksic, Julian Maller, Rachel Nguyen, Utku Norman, J. Jay Gargus, Donna M. Werling, David J. Cutler, Silvia De Rubeis, Kathryn Roeder, Ryan N. Doan, Sherif Gerges, Joseph D. Buxbaum, Per Magnus, Patrick Turley, Moyra Smith, Isaac N. Pessah, Rebecca J. Schmidt, Chiara Fallerini, Michael E. Talkowski, Carla Lintas, Pål Surén, Paige M. Siper, Duncan S. Palmer, Timothy W. Yu, Michael S. Breen, Sven Sandin, Esben Agerbo, Rich Belliveau, Antonio M. Persico, Elaine Cristina Zachi, Matthew W. State, Karoline Teufel, Margaret A. Pericak-Vance, Caitlin E. Carey, Ryan Collins, Lambertus Klei, Lara Tang, Mads V. Hollegaard, Ole Mors, Iuliana Ionita-Laza, Elisa Giorgio, Astanand Jugessur, Gerry Schellenberg, Christopher A. Walsh, A. Ercument Cicek, Caroline Dias, Gun Peggy Knudsen, Louise Gallagher, Elise B. Robinson, Abraham Reichenberg, Judith Miller, Ashley Dumont, Flora Tassone, Grace Schwartz, Peter Szatmari, Jacqueline I. Goldstein, Evelise Riberi, Brian H.Y. Chung, Stephen W. Scherer, Fátima Lopes, Jesslyn Jamison, Thomas Werge, Mara Parellada, Gabriela Soares, Hilary Coon, Shan Dong, Terho Lehtimäki, Norio Ozaki, Lauren A. Weiss, Susan L. Santangelo, F. Kyle Satterstrom, Daniel P. Howrigan, Emily Hansen-Kiss, Anders D. Børglum, Vivek Appadurai, Maria Rita Passos-Bueno, Hailiang Huang, Marcus C.Y. Chan, Eric M. Morrow, Stephen J. Guter, Catalina Betancur, Ditte Demontis, Matthew W. Mosconi, Pierandrea Muglia, Joanna Martin, Jack A. Kosmicki, Christine M. Freitag, Suma Jacob, W. Ian Lipkin, Angel Carracedo, Mark J. Daly, Andreas G. Chiocchetti, Eduarda Montenegro M. de Souza, Carsten Bøcker Pedersen, Isabela Maya Wahys Silva, Elizabeth E. Guerrero, Mafalda Barbosa, A. Jeremy Willsey, Maureen Mulhern, Claire Churchhouse, Raymond K. Walters, Timothy Poterba, Alessandra Renieri, Emilie M. Wigdor, Lauren M. Schmitt, Jennifer L. Moran, Mullin H.C. Yu, Edwin H. Cook, Jiebiao Wang, Behrang Mahjani, Kaitlin E. Samocha, Kaija Puura, Xin He, Ezra Susser, Aarno Palotie, Bernardo Dalla Bernardina, Montserrat Fernández-Prieto, Thomas Damm Als, Mykyta Artomov, Emma Wilkinson, Mads E. Hauberg, Enrico Domenici, Joon Yong An, Christine Søholm Hansen, Somer L. Bishop, Idan Menashe, So Lun Lee, Marianne Giørtz Pedersen, Alfredo Brusco, Nancy J. Minshew, Michael E. Zwick, Jesper Buchhave Poulsen, Elaine T. Lim, Benjamin M. Neale, Harrison Brand, Danielle Halpern, Elisabetta Trabetti, Alexander Kolevzon, Christine Stevens, Aurora Currò, Miia Kaartinen, Gal Meiri, Richard Anney, Søren Dalsgaard, Minshi Peng, Kimberly Chambert, Brooke Sheppard, Yunin Ludena, James S. Sutcliffe, Marie Bækvad-Hansen, Xinyi Xu, Audrey Thurm, Itaru Kushima, Michael Gill, Irva Hertz-Picciotto, Jonatan Pallesen, Stephan Ripke, Dara S. Manoach, Giovanni Battista Ferrero, Nell Maltman, Michael L. Cuccaro, David M. Hougaard, Javier González-Peñas, Wesley K. Thompson, Felecia Cerrato, Danielle de Paula Moreira, Jonas Bybjerg-Grauholm, Alicia R. Martin, Merete Nordentoft, John A. Sweeney, Alfonso Buil, Tarjinder Singh, Bernie Devlin, Jakob Grove, Daniel H. Geschwind, Manuel Mattheisen, Patrícia Maciel, Preben Bo Mortensen, Andrew J. Schork, Ryan Yuen, Christina M. Hultman, Maria del Pilar Trelles, Aparna Bhaduri, Sabine Schlitt, Diego Lopergolo, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Carnegie Mellon University [Pittsburgh] (CMU), Icahn School of Medicine at Mount Sinai [New York] (MSSM), University of California [San Francisco] (UCSF), University of California, Korea University [Seoul], The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University [Aarhus], Center for Genomics and Personalized Medicine [Aarhus, Denmark] (CGPM), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research [San Francisco, CA, USA], Bilkent University [Ankara], University of California [Irvine] (UCI), Medical Investigation of Neurodevelopmental Disorders Institute [Davis, CA, USA] (MIND), University of California [Davis] (UC Davis), University of California-University of California, Boston Children's Hospital, Génétique de l'autisme = Genetics of Autism (NPS-01), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), University of Illinois [Chicago] (UIC), University of Illinois System, Trinity College Dublin, Vanderbilt University School of Medicine [Nashville], National Institute of Mental Health (NIMH), Emory University School of Medicine, Emory University [Atlanta, GA], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Autism Sequencing Consortium : Branko Aleksic, Richard Anney, Mafalda Barbosa, Somer Bishop, Alfredo Brusco, Jonas Bybjerg-Grauholm, Angel Carracedo, Marcus C.Y. Chan, Andreas G. Chiocchetti, Brian H.Y. Chung, Hilary Coon, Michael L. Cuccaro, Aurora Curro´ , Bernardo Dalla Bernardina, Ryan Doan, Enrico Domenici, Shan Dong, Chiara Fallerini, Montserrat Ferna´ ndez-Prieto, Giovanni Battista Ferrero, Christine M. Freitag, Menachem Fromer, J. Jay Gargus, Daniel Geschwind, Elisa Giorgio, Javier Gonza´ lez-Pen˜ as, Stephen Guter, Danielle Halpern, Emily HansenKiss, Xin He, Gail E. Herman, Irva Hertz-Picciotto, David M. Hougaard, Christina M. Hultman, Iuliana Ionita-Laza, Suma Jacob, Jesslyn Jamison, Astanand Jugessur, Miia Kaartinen, Gun Peggy Knudsen, Alexander Kolevzon, Itaru Kushima, So Lun Lee, Terho Lehtima¨ ki, Elaine T. Lim, Carla Lintas, W. Ian Lipkin, Diego Lopergolo, Fa´ tima Lopes, Yunin Ludena, Patricia Maciel, Per Magnus, Behrang Mahjani, Nell Maltman, Dara S. Manoach, Gal Meiri, Idan Menashe, Judith Miller, Nancy Minshew, Eduarda M.S. Montenegro, Danielle Moreira, Eric M. Morrow, Ole Mors, Preben Bo Mortensen, Matthew Mosconi, Pierandrea Muglia, Benjamin M. Neale, Merete Nordentoft, Norio Ozaki, Aarno Palotie, Mara Parellada, Maria Rita Passos-Bueno, Margaret Pericak-Vance, Antonio M. Persico, Isaac Pessah, Kaija Puura, Abraham Reichenberg, Alessandra Renieri, Evelise Riberi, Elise B. Robinson, Kaitlin E. Samocha, Sven Sandin, Susan L. Santangelo, Gerry Schellenberg, Stephen W. Scherer, Sabine Schlitt, Rebecca Schmidt, Lauren Schmitt, Isabela M.W. Silva, Tarjinder Singh, Paige M. Siper, Moyra Smith, Gabriela Soares, Camilla Stoltenberg, Pa˚ l Suren, Ezra Susser, John Sweeney, Peter Szatmari, Lara Tang, Flora Tassone, Karoline Teufel, Elisabetta Trabetti, Maria del Pilar Trelles, Christopher A. Walsh, Lauren A. Weiss, Thomas Werge, Donna M. Werling, Emilie M. Wigdor, Emma Wilkinson, A. Jeremy Willsey, Timothy W. Yu, Mullin H.C. Yu, Ryan Yuen, and Elaine Zachi. and iPSYCH-Broad Consortium : e Esben Agerbo, Thomas Damm Als, Vivek Appadurai, Marie Bækvad-Hansen, Rich Belliveau, Alfonso Buil, Caitlin E. Carey, Felecia Cerrato, Kimberly Chambert, Claire Churchhouse, Søren Dalsgaard, Ditte Demontis, Ashley Dumont, Jacqueline Goldstein, Christine S. Hansen, Mads Engel Hauberg, Mads V. Hollegaard, Daniel P. Howrigan, Hailiang Huang, Julian Maller, Alicia R. Martin, Joanna Martin, Manuel Mattheisen, Jennifer Moran, Jonatan Pallesen, Duncan S. Palmer, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Timothy Poterba, Jesper Buchhave Poulsen, Stephan Ripke, Andrew J. Schork, Wesley K. Thompson, Patrick Turley, and Raymond K. Walters., Norman, Utku, Çicek, A. Ercüment, Betancur, Catalina, University of California [San Francisco] (UC San Francisco), University of California (UC), University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki
Subjects: Male, INTELLECTUAL DISABILITY, genetic structures, MESH: Neurons, Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, Whole Exome Sequencing, Cohort Studies, 0302 clinical medicine, Gene Frequency, Neurobiology, MESH: Gene Expression Regulation, Developmental, Spectrum disorder, Exome, Developmental, genetics, Copy-number variation, excitatory-inhibitory balance, MESH: Cohort Studies, Exome sequencing, Genetics, Cerebral Cortex, Neurons, 0303 health sciences, MESH: Exome, autism spectrum disorder, cell type, cytoskeleton, excitatory neurons, exome sequencing, inhibitory neurons, liability, neurodevelopment, MESH: Genetic Predisposition to Disease, MESH: Case-Control Studies, Phenotype, Autism spectrum disorder, Female, Single-Cell Analysis, AGED 8 YEARS, MESH: Autistic Disorder, UNITED-STATES, GENETIC RISK, Biology, MESH: Phenotype, behavioral disciplines and activities, SAND DOMAIN, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Sex Factors, MESH: Sex Factors, MESH: Whole Exome Sequencing, MESH: Neurobiology, mental disorders, medicine, MESH: Gene Frequency, Humans, Cell Lineage, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Autistic Disorder, Allele frequency, Case-Control Studies, Mutation, Missense, Gene Expression Regulation, Developmental, SPECTRUM DISORDER, COPY NUMBER VARIATION, 030304 developmental biology, MESH: Mutation, Missense, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Cell Lineage, medicine.disease, MESH: Male, MESH: Cerebral Cortex, DISABILITIES MONITORING NETWORK, Gene Expression Regulation, DE-NOVO MUTATIONS, Mutation, Autism, Missense, MESH: Female, 030217 neurology & neurosurgery, MESH: Single-Cell Analysis
Abstract: International audience; We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.
Published: 2020

10. An interactome perturbation framework prioritizes damaging missense mutations for developmental disorders

Author: Bernie Devlin, Jiebiao Wang, Siwei Chen, Kathryn Roeder, Yuan Liu, Haiyuan Yu, Robert Fragoza, and Lambertus Klei
Subjects: Male, 0301 basic medicine, Proband, Autism Spectrum Disorder, Developmental Disabilities, Mutation, Missense, Functional impact, Biology, Interactome, Article, 03 medical and health sciences, Human interactome, Genetics, medicine, Humans, Missense mutation, Genetic Predisposition to Disease, Autistic Disorder, Child, Gene, Integrated approach, medicine.disease, 030104 developmental biology, Autism, Female
Abstract: Identifying disease-associated missense mutations remains a challenge, especially in large-scale sequencing studies. Here we establish an experimentally and computationally integrated approach to investigate the functional impact of missense mutations in the context of the human interactome network and test our approach by analyzing ~2,000 de novo missense mutations found in autism subjects and their unaffected siblings. Interaction-disrupting de novo missense mutations are more common in autism probands, principally affect hub proteins, and disrupt a significantly higher fraction of hub interactions than in unaffected siblings. Moreover, they tend to disrupt interactions involving genes previously implicated in autism, providing complementary evidence that strengthens previously identified associations and enhances the discovery of new ones. Importantly, by analyzing de novo missense mutation data from six disorders, we demonstrate that our interactome perturbation approach offers a generalizable framework for identifying and prioritizing missense mutations that contribute to the risk of human disease.
Published: 2018

11. Heritable Variation, With Little or No Maternal Effect, Accounts for Recurrence Risk to Autism Spectrum Disorder in Sweden

Author: Benjamin Hon Kei Yip, Kathryn Roeder, Bernie Devlin, Yudi Pawitan, Lambertus Klei, Sven Sandin, Behrang Mahjani, Abraham Reichenberg, Dan Bai, Joseph D. Buxbaum, Christina M. Hultman, and Dorothy E. Grice
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Adolescent, Autism Spectrum Disorder, Epidemiology, Autism, Population, Mothers, Environment, Population-based, Article, Cohort Studies, Heritability, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Spectrum disorder, Registries, Sibling, Child, Psychiatry, education, Biological Psychiatry, Pervasive developmental disorder not otherwise specified, Sweden, education.field_of_study, Maternal effect, medicine.disease, 3. Good health, 030104 developmental biology, Autism spectrum disorder, Female, Psychology, 030217 neurology & neurosurgery, Demography
Abstract: Background Autism spectrum disorder (ASD) has both genetic and environmental origins, including potentially maternal effects. Maternal effects describe the association of one or more maternal phenotypes with liability to ASD in progeny that are independent of maternally transmitted risk alleles. While maternal effects could play an important role, consistent with association to maternal traits such as immune status, no study has estimated maternal, additive genetic, and environmental effects in ASD. Methods Using a population-based sample consisting of all children born in Sweden from 1998 to 2007 and their relatives, we fitted statistical models to family data to estimate the variance in ASD liability originating from maternal, additive genetic, and shared environmental effects. We calculated sibling and cousin family recurrence risk ratio as a direct measure of familial, genetic, and environmental risk factors and repeated the calculations on diagnostic subgroups, specifically autistic disorder (AD) and spectrum disorder (SD), which included Asperger’s syndrome and/or pervasive developmental disorder not otherwise specified. Results The sample consisted of 776,212 children of whom 11,231 had a diagnosis of ASD: 4554 with AD, 6677 with SD. We found support for large additive genetic contribution to liability; heritability (95% confidence interval [CI]) was estimated to 84.8% (95% CI: 73.1–87.3) for ASD, 79.6% (95% CI: 61.2–85.1) for AD, and 76.4% (95% CI: 63.0–82.5) for SD. Conclusions There was modest, if any, contribution of maternal effects to liability for ASD, including subtypes AD and SD, and there was no support for shared environmental effects. These results show liability to ASD arises largely from additive genetic variation.
Published: 2018

12. Cohort profile: Epidemiology and Genetics of Obsessive-compulsive disorder and chronic tic disorders in Sweden (EGOS)

Author: Gun Karlsson, Christina M. Hultman, Lambertus Klei, Bernie Devlin, Jennifer Reichert, Sven Sandin, Dorothy E. Grice, Joseph D. Buxbaum, Aki Tuuliainen, Christina Gustavsson Mahjani, Silvia De Rubeis, Anna-Carin Säll Grahnat, Karin Dellenvall, Behrang Mahjani, and Abraham Reichenberg
Subjects: medicine.medical_specialty, Obsessive-Compulsive Disorder, Health (social science), Social Psychology, Epidemiology, Population, Tourette syndrome, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, education, Sampling bias, Genetics, Sweden, education.field_of_study, business.industry, Confounding, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Tic Disorders, Cohort, Etiology, business, Tourette Syndrome
Abstract: The EGOS study (Epidemiology and Genetics of Obsessive–compulsive disorder and chronic tic disorders in Sweden) is a large-scale, epidemiological, prospective cohort that is used to identify genetic and environmental risk factors in the etiology of obsessive–compulsive disorder (OCD) and chronic tic disorders (CTD). Individuals born between January 1954 and December 1998 with at least two diagnoses of OCD or CTD at different timepoints in the National Patient Register (NPR), and followed between January 1997 and December 2012, represent the EGOS source population (n = 20,374). The Swedish Multi-Generation Registry (MGR) are then used to define family relatedness for all cases and additional phenotypic and demographic data added to the resultant database. To create an epidemiologically valid subset of the source cohort that also includes biospecimens and additional phenotyping, we contact cases from within the source population. To date, 6832 invitations have been sent out and 1853 (27%) have elected to participate in the EGOS biospecimen collection. To date, 1608 biological samples have been collected, of which 1249 are genotyped and 832 supplementary Obsessive–Compulsive Inventory-Revised (OCI-R) and/or Florida Obsessive–Compulsive Inventory (FOCI) have been completed by individuals with OCD and/or CTD, age 16–64 years. DNA samples are genotyped using Infinium Global Screening Array and will undergo whole-exome sequencing in the future. Detailed information is available for each individual through linkage to the Swedish national registers, e.g., identification of additional psychiatric diagnoses, medical diagnoses, birth-related variables, and relevant demographic and social data. EGOS benefits from a genetically homogeneous sample with epidemiological ascertainment, minimizing the risk of confounding due to population stratification on ascertainment bias. In addition, this study is built upon clinical diagnoses of OCD and CTD in specialized psychiatric care, which reduces further biases and case misclassification.
Published: 2019

13. Whole-genome and RNA sequencing reveal variation and transcriptomic coordination in the developing human prefrontal cortex

Author: Michael C. Gilson, Forrest O. Gulden, Zhen Li, Jean-Leon Thomas, Claudia Dastmalchi, Stephen Sanders, Joseph D. Buxbaum, Matthew W. State, Donna M. Werling, Minshi Peng, Navjot Kaur, André M. M. Sousa, Kathryn Roeder, Ian A. Glass, Michael E. Talkowski, Lambertus Klei, Diana R. O’Day, Shan Dong, Lindsay Liang, Xuefang Zhao, Sirisha Pochareddy, Kimberly A. Aldinger, Brooke Sheppard, Bernie Devlin, Gabriel Santpere, A. Ercument Cicek, Homa Adle-Biassette, Joon Yong An, Andrew T.N. Tebbenkamp, Jinmyung Choi, Noah Zaitlen, Michael S. Breen, Nenad Sestan, and Çiçek, A. Ercüment
Subjects: 0301 basic medicine, PsychENCODE, Medical Physiology, DLPFC, Genome, Whole Exome Sequencing, Transcriptome, 0302 clinical medicine, fetal transition, Databases, Genetic, Gene expression, 2.1 Biological and endogenous factors, Aetiology, Prefrontal cortex, lcsh:QH301-705.5, Pediatric, Genetics, dorsolateral prefrontal cortex, 0303 health sciences, Brain, Genomics, Single Nucleotide, Human Fetal Tissue, Phenotype, medicine.anatomical_structure, prenatal eQTL, Prenatal eQTL, mTOR, Dorsolateral prefrontal cortex, BrainVar, Haploinsufficiency, Sequence Analysis, Neurotypical, Biotechnology, Quantitative Trait Loci, Prefrontal Cortex, LOC101926933 RP11-298I3.1 AL132780.1 ENSG00000257285, Biology, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Databases, 03 medical and health sciences, Genetic, Exome Sequencing, medicine, Humans, Genetic Predisposition to Disease, RHEBL1, Polymorphism, Gene, 030304 developmental biology, Whole genome sequencing, Base Sequence, Whole Genome Sequencing, Sequence Analysis, RNA, Human Genome, Neurosciences, Computational Biology, Genetic Variation, Fetal transition, Brain Disorders, 030104 developmental biology, lcsh:Biology (General), Expression quantitative trait loci, RNA, Biochemistry and Cell Biology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: SUMMARY Gene expression levels vary across developmental stage, cell type, and region in the brain. Genomic variants also contribute to the variation in expression, and some neuropsychiatric disorder loci may exert their effects through this mechanism. To investigate these relationships, we present BrainVar, a unique resource of paired whole-genome and bulk tissue RNA sequencing from the dorsolateral prefrontal cortex of 176 individuals across prenatal and postnatal development. Here we identify common variants that alter gene expression (expression quantitative trait loci [eQTLs]) constantly across development or predominantly during prenatal or postnatal stages. Both “constant” and “temporal-predominant” eQTLs are enriched for loci associated with neuropsychiatric traits and disorders and colocalize with specific variants. Expression levels of more than 12,000 genes rise or fall in a concerted late-fetal transition, with the transitional genes enriched for cell-type-specific genes and neuropsychiatric risk loci, underscoring the importance of cataloging developmental trajectories in understanding cortical physiology and pathology., In Brief Werling et al. analyze gene expression across the span of human cerebral cortical development and profile the trajectories of individual genes, coordinated groups of genes, and their relationships to disorders. Integration of genetic variation identifies quantitative trait loci that implicate specific genes in loci associated with neuropsychiatric traits and disorders., Graphical Abstract
Published: 2019

14. Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism

Author: Evelise Riber, Suma Jacob, Isabela Maya Wahys Silva, Edwin H. Cook, Jennifer Reichert, Merete Nordentoft, Jiebiao Wang, Kaitlin E. Samocha, John A. Sweeney, Elaine Cristina Zachi, Brooke Sheppard, Yunin Ludena, Maureen Mulhern, Lambertus Klei, Christina M. Hultman, Branko Aleksic, Paige M. Siper, Nell Maltman, Fátima Lopes, Jesslyn Jamison, Astanand Jugessur, Timothy W. Yu, F. Kyle Satterstrom, Tarjinder Singh, Bernie Devlin, Per Magnus, Mara Parellada, Louise Gallagher, Christine Stevens, Susan L. Santangelo, David J. Cutler, Shan Dong, Margaret A. Pericak-Vance, Norio Ozaki, Camilla Stoltenberg, Matthew W. State, Emma Wilkinson, Lauren A. Weiss, Michael L. Cuccaro, Stephen Sanders, Aparna Bhaduri, Brian H.Y. Chung, Maria del Pilar Trelles, Ezra Susser, Somer L. Bishop, Catalina Betancur, Donna M. Werling, Sabine Schlitt, Diego Lopergolo, Abraham Reichenberg, Judith Miller, Gabriela Soares, Karoline Teufel, David M. Hougaard, Enrico Domenici, Thomas Werge, Terho Lehtimäki, Sherif Gerges, Audrey Thurm, Emily Hansen-Kiss, Christopher T. Walsh, Michael Gill, Maria Rita Passos-Bueno, Aurora Currò, Utku Norman, Nancy J. Minshew, Harrison Brand, Elisa Giorgio, A. Ercument Cicek, Elaine T. Lim, Joseph D. Buxbaum, Chiara Fallerini, Caroline Dias, Miia Kaartinen, Gal Meiri, Rachel Nguyen, Isaac N. Pessah, J. Jay Gargus, Ryan N. Doan, Minshi Peng, Matthew W. Mosconi, Elizabeth E. Guerrero, Michael E. Talkowski, Iuliana Ionita-Laza, Carla Lintas, Gerry Schellenberg, Alessandra Renieri, Marcus C.Y. Chan, Stephen J. Guter, Danielle Halpern, Javier González-Peñas, Flora Tassone, So Lun Lee, Elise B. Robinson, Alfredo Brusco, Danielle de Paula Moreira, Bernardo Dalla Bernardina, Benjamin M. Neale, Gun Peggy Knudsen, Behrang Mahjani, Peter Szatmari, Elisabetta Trabetti, Lauren M. Schmitt, Kaija Puura, Mykyta Artomov, Rebecca J. Schmidt, Michael S. Breen, Mark J. Daly, Joon Yong An, Dara S. Manoach, Grace Schwartz, Hilary Coon, Christine M. Freitag, Andreas G. Chiocchetti, Eduarda Montenegro M. de Souza, Ryan L. Collins, Mafalda Barbosa, Emilie M. Wigdor, Montserrat Fernández-Prieto, Stephen W. Scherer, Anders D. Børglum, Jack A. Kosmicki, W. Ian Lipkin, Mullin H.C. Yu, Michael E. Zwick, Irva Hertz-Picciotto, Kathryn Roeder, Moyra Smith, Gail E. Herman, James S. Sutcliffe, Xinyi Xu, A. Jeremy Willsey, Alexander Kolevzon, Itaru Kushima, Menachem Fromer, Jakob Grove, Patrícia Maciel, Preben Bo Mortensen, Xin He, Aarno Palotie, Silvia De Rubeis, Idan Menashe, Jonas Bybjerg-Grauholm, Pål Surén, Antonio M. Persico, Ole Mors, Sven Sandin, Lara Tang, Eric M. Morrow, Pierandrea Muglia, Angel Carracedo, Ryan Yuen, and Giovanni Battista Ferrero
Subjects: False discovery rate, Regulation of gene expression, Genetics, 0303 health sciences, Biology, medicine.disease, Phenotype, 03 medical and health sciences, 0302 clinical medicine, Autism spectrum disorder, mental disorders, medicine, Autism, Copy-number variation, Gene, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract: We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.
Published: 2019

15. Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder

Author: A. Jeremy Willsey, Lindsay Liang, Aaron R. Quinlan, Clif Duhn, Bernie Devlin, Benjamin Currall, Stephen Sanders, Gabor T. Marth, Xuefang Zhao, Kathryn Roeder, Shan Dong, Donna M. Werling, Lingxue Zhu, Mark J. Daly, Joon Yong An, Claudia Dastmalchi, Lambertus Klei, Michael C. Gilson, Harrison Brand, Young Shin Kim, Matthew W. State, Eirene Markenscoff-Papadimitriou, Sirisha Pochareddy, Benjamin M. Neale, Kevin Lin, John L.R. Rubenstein, Nenad Sestan, Harold Z. Wang, Michael E. Talkowski, Jeanselle Dea, Ryan L. Collins, Grace Schwartz, Hilary Coon, Joseph D. Buxbaum, and Nadav Ahituv
Subjects: 0301 basic medicine, Risk, General Science & Technology, Autism Spectrum Disorder, Intellectual and Developmental Disabilities (IDD), Autism, DNA Mutational Analysis, Context (language use), Biology, medicine.disease_cause, Genome, Article, Conserved sequence, Promoter Regions, 03 medical and health sciences, Genetic, Genetic variation, Genetics, medicine, 2.1 Biological and endogenous factors, Humans, Aetiology, Promoter Regions, Genetic, Conserved Sequence, Pediatric, Mutation, Multidisciplinary, Binding Sites, Human Genome, Genetic Variation, medicine.disease, Brain Disorders, Pedigree, DNA binding site, Mental Health, 030104 developmental biology, Autism spectrum disorder, Genetic Loci, Biotechnology, Transcription Factors
Abstract: INTRODUCTION The DNA of protein-coding genes is transcribed into mRNA, which is translated into proteins. The “coding genome” describes the DNA that contains the information to make these proteins and represents ~1.5% of the human genome. Newly arising de novo mutations (variants observed in a child but not in either parent) in the coding genome contribute to numerous childhood developmental disorders, including autism spectrum disorder (ASD). Discovery of these effects is aided by the triplet code that enables the functional impact of many mutations to be readily deciphered. In contrast, the “noncoding genome” covers the remaining ~98.5% and includes elements that regulate when, where, and to what degree protein-coding genes are transcribed. Understanding this noncoding sequence could provide insights into human disorders and refined control of emerging genetic therapies. Yet little is known about the role of mutations in noncoding regions, including whether they contribute to childhood developmental disorders, which noncoding elements are most vulnerable to disruption, and the manner in which information is encoded in the noncoding genome. RATIONALE Whole-genome sequencing (WGS) provides the opportunity to identify the majority of genetic variation in each individual. By performing WGS on 1902 quartet families including a child affected with ASD, one unaffected sibling control, and their parents, we identified ~67 de novo mutations across each child’s genome. To characterize the functional role of these mutations, we integrated multiple datasets relating to gene function, genes implicated in neurodevelopmental disorders, conservation across species, and epigenetic markers, thereby combinatorially defining 55,143 categories. The scope of the problem—testing for an excess of de novo mutations in cases relative to controls for each category—is challenging because there are more categories than families. RESULTS Comparing cases to controls, we observed an excess of de novo mutations in cases in individual categories in the coding genome but not in the noncoding genome. To overcome the challenge of detecting noncoding association, we used machine learning tools to develop a de novo risk score to look for an excess of de novo mutations across multiple categories. This score demonstrated a contribution to ASD risk from coding mutations and a weaker, but significant, contribution from noncoding mutations. This noncoding signal was driven by mutations in the promoter region, defined as the 2000 nucleotides upstream of the transcription start site (TSS) where mRNA synthesis starts. The strongest promoter signals were defined by conservation across species and transcription factor binding sites. Well-defined promoter elements (e.g., TATA-box) are usually observed within 80 nucleotides of the TSS; however, the strongest ASD association was observed distally, 750 to 2000 nucleotides upstream of the TSS. CONCLUSION We conclude that de novo mutations in the noncoding genome contribute to ASD. The clearest evidence of noncoding ASD association came from mutations at evolutionarily conserved nucleotides in the promoter region. The enrichment for transcription factor binding sites, primarily in the distal promoter, suggests that these mutations may disrupt gene transcription via their interaction with enhancer elements in the promoter region, rather than interfering with transcriptional initiation directly. Promoter regions in autism. De novo mutations from 1902 quartet families are assigned to 55,143 annotation categories, which are each assessed for autism spectrum disorder (ASD) association by comparing mutation counts in cases and sibling controls. A de novo risk score demonstrated a noncoding contribution to ASD driven by promoter mutations, especially at sites conserved across species, in the distal promoter or targeted by transcription factors.
Published: 2018

16. 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 GiÃ¸rtz, Pedersen, Carsten BÃ¸cker, 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 SÃ¸holm, 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, PatrÃcia 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., BÃ¦kvad-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

17. Analysis of Shared Haplotypes amongst Palauans Maps Loci for Psychotic Disorders to 4q28 and 5q23-q31

Author: William Byerley, Bernie Devlin, Josepha Tiobech, Lambertus Klei, Victor Yano, Marina Myles-Worsley, Kathryn Roeder, Nadine M. Melhem, Stephen V. Faraone, Youeun Song, Frank A. Middleton, Corneliu A. Bodea, and Pearl Marumoto
Subjects: Genetics, Original Paper, education.field_of_study, Population, Haplotype, General Medicine, Biology, medicine.disease, Penetrance, Identity by descent, Genome, Genetic linkage, Schizophrenia, Genetic variation, medicine, education
Abstract: To localize genetic variation affecting risk for psychotic disorders in the population of Palau, we genotyped DNA samples from 203 Palauan individuals diagnosed with psychotic disorders, broadly defined, and 125 control subjects using a genome-wide single nucleotide polymorphism array. Palau has unique features advantageous for this study: due to its population history, Palauans are substantially interrelated; affected individuals often, but not always, cluster in families; and we have essentially complete ascertainment of affected individuals. To localize risk variants to genomic regions, we evaluated long-shared haplotypes, ≥10 Mb, identifying clusters of affected individuals who share such haplotypes. This extensive sharing, typically identical by descent, was significantly greater in cases than population controls, even after controlling for relatedness. Several regions of the genome exhibited substantial excess of shared haplotypes for affected individuals, including 3p21, 3p12, 4q28, and 5q23-q31. Two of these regions, 4q28 and 5q23-q31, showed significant linkage by traditional LOD score analysis and could harbor variants of more sizeable risk for psychosis or a multiplicity of risk variants. The pattern of haplotype sharing in 4q28 highlights PCDH10, encoding a cadherin-related neuronal receptor, as possibly involved in risk.
Published: 2016

18. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism

Author: Shan Dong, Norio Ozaki, Ryan K. C. Yuen, David J. Cutler, Lauren A. Weiss, Catalina Betancur, Abraham Reichenberg, Hassen-Kiss E, Judith Miller, Brooke Sheppard, Yunin Ludena, Astanand Jugessur, Irva Hertz-Picciotto, Donna M. Werling, Aurora Currò, Isaac N. Pessah, Giovanni Battista Ferrero, Somer L. Bishop, Utku Norman, Nancy J. Minshew, Tarjinder Singh, Bernie Devlin, Michael E. Talkowski, Carla Lintas, Susan L. Santangelo, Miia Kaartinen, Gal Meiri, Camilla Stoltenberg, Stephen Sanders, Sherif Gerges, Michael L. Cuccaro, Ryan N. Doan, Suma Jacob, Matthew W. Mosconi, Lambertus Klei, Michael E. Zwick, Kathryn Roeder, Merete Nordentoft, Lauren M. Schmitt, John A. Sweeney, Elizabeth E. Guerrero, Kaija Puura, Alessandra Renieri, Elaine T. Lim, Maureen Mulhern, Danielle de Paula Moreira, Cicek Ae, Nell Maltman, Aparna Bhaduri, Mara Parellada, Sabine Schlitt, Diego Lopergolo, Gun Peggy Knudsen, Christina M. Hultman, Jesslyn Jamison, Rebecca J. Schmidt, So Lun Lee, Iuliana Ionita-Laza, Peter Szatmari, Gerry Schellenberg, Alfredo Brusco, Christine M. Freitag, Andreas G. Chiocchetti, Javier González-Peñas, Michael S. Breen, Jakob Grove, Ryan L. Collins, Mafalda Barbosa, Emilie M. Wigdor, Elise B. Robinson, Cathy A. Stevens, Gabriela Soares, Benjamin M. Neale, Edwin H. Cook, Jiebiao Wang, David M. Hougaard, Enrico Domenici, Gail E. Herman, Patrícia Maciel, Kaitlin E. Samocha, Preben Bo Mortensen, Stephen W. Scherer, Yu Mhc, Elaine Cristina Zachi, Menachem Fromer, Antonio M. Persico, Anders D. Børglum, Minshi Peng, Megan Smith, Elisabetta Trabetti, Rachel Nguyen, Fátima Lopes, James S. Sutcliffe, Trelles Mdp, Xinyi Xu, Emma Wilkinson, Joseph D. Buxbaum, Audrey Thurm, Chiara Fallerini, Jack A. Kosmicki, Michael Gill, Paige M. Siper, Timothy W. Yu, Grace Schwartz, Thomas Werge, Terho Lehtimäki, Itaru Kushima, Jay Gargus, Dalla Bernardina B, Hilary Coon, Maria Rita Passos-Bueno, Stephen J. Guter, Margaret A. Pericak-Vance, Matthew W. State, Per Magnus, Christopher A. Walsh, Evelise Riberi, Ezra Susser, Xin He, Aarno Palotie, Idan Menashe, Eric M. Morrow, Jonas Bybjerg-Grauholm, Pierandrea Muglia, Pål Surén, De Rubeis S, Angel Carracedo, Sven Sandin, Montse Fernández-Prieto, Lara Tang, Lipkin Wi, Ole Mors, Louise Gallagher, Montenegro M. de Souza E, Brian H.Y. Chung, Anney Rjl, Alexander Kolevzon, Dara S. Manoach, Daniel H. Geschwind, Silva Imw, Caroline Dias, Jeremy Willsey, Jennifer Reichert, Elisa Giorgio, Branko Aleksic, Flora Tassone, Satterstrom Fk, Senthil G, Karoline Teufel, Chan Mcy, Harrison Brand, Danielle Halpern, Behrang Mahjani, Mykyta Artomov, Mark J. Daly, Joon Yong An, and Lehner T
Subjects: Genetics, Regulation of gene expression, 0303 health sciences, medicine.medical_specialty, Neurogenetics, Biology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Autism spectrum disorder, mental disorders, medicine, Autism, Medical genetics, Copy-number variation, Gene, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract: SummaryWe present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.
Published: 2018
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19. An analytical framework for whole genome sequence association studies and its implications for autism spectrum disorder

Author: Donna M. Werling, Ryan M. Layer, Robert E. Handsaker, Matthew W. State, Carolyn A. Erdman, Tomasz J. Nowakowski, Michael C. Gilson, Stephen Sanders, Arnold R. Kriegstein, Eirene Markenscoff-Papadimitriou, Sirisha Pochareddy, Lambertus Klei, A. Jeremy Willsey, Seva Kashin, Xin He, Harold Z. Wang, Michael E. Talkowski, Shan Dong, Michael F. Walker, Lingxue Zhu, Bernie Devlin, Steven A. McCarroll, Kathryn Roeder, Benjamin Currall, Matthew J. Waterman, Clif Duhn, John L.R. Rubenstein, Joseph D. Buxbaum, Gabor T. Marth, Aaron R. Quinlan, Matthew R. Stone, Louw Smith, Xuefang Zhao, Mark J. Daly, Joon Yong An, Harrison Brand, Joseph T. Glessner, Benjamin M. Neale, Jeffrey D. Mandell, Andrew Farrell, Nenad Sestan, Yuwen Liu, Grace Schwartz, Hilary Coon, Jeanselle Dea, Rachita Yadav, and Ryan L. Collins
Subjects: 0301 basic medicine, Whole genome sequencing, Autism Spectrum Disorder, Genomics, Genome-wide association study, Computational biology, Biology, medicine.disease, Article, Structural variation, 03 medical and health sciences, 030104 developmental biology, Autism spectrum disorder, Multiple comparisons problem, Genetics, medicine, Autism, Humans, Genetic association, Genome-Wide Association Study
Abstract: Genomic association studies of common or rare protein-coding variation have established robust statistical approaches to account for multiple testing. Here we present a comparable framework to evaluate rare and de novo noncoding single-nucleotide variants, insertion/deletions, and all classes of structural variation from whole-genome sequencing (WGS). Integrating genomic annotations at the level of nucleotides, genes, and regulatory regions, we define 51,801 annotation categories. Analyses of 519 autism spectrum disorder families did not identify association with any categories after correction for 4,123 effective tests. Without appropriate correction, biologically plausible associations are observed in both cases and controls. Despite excluding previously identified gene-disrupting mutations, coding regions still exhibited the strongest associations. Thus, in autism, the contribution of de novo noncoding variation is probably modest in comparison to that of de novo coding variants. Robust results from future WGS studies will require large cohorts and comprehensive analytical strategies that consider the substantial multiple-testing burden.
Published: 2018

20. Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci

Author: Eric Fombonne, Stephen Sanders, Rita M. Cantor, Bernie Devlin, Shan Dong, Kathryn Roeder, Catherine Lord, Mack Y. Su, David H. Ledbetter, Arthur P. Goldberg, Vanessa H. Bal, Nicole A. Teran, Eric M. Morrow, Cai Jinlu, James S. Sutcliffe, Michael F. Walker, Jeffrey D. Mandell, Edwin H. Cook, Elise B. Robinson, Mark J. Daly, Kaitlin E. Samocha, Xin He, Christa Lese Martin, Timothy W. Yu, Donna M. Werling, Donna M. Martin, Arthur L. Beaudet, Michael E. Talkowski, Michael T. Murtha, Joseph D. Buxbaum, John F. Keaney, Dorothy E. Grice, A. Ercument Cicek, A. Jeremy Willsey, Somer L. Bishop, Christopher S. Poultney, Lambertus Klei, Matthew W. State, Daniel Moreno-De-Luca, Louw Smith, A. Gulhan Ercan-Sencicek, Shrikant Mane, Tor Solli-Nowlan, Christopher A. Walsh, Daniel H. Geschwind, and Jennifer K. Lowe
Subjects: Male, Gene duplication, Genotype, Autism Spectrum Disorder, Autism, Neuroscience(all), Single-nucleotide polymorphism, Major clinical study, Gene sequence, Biology, Gene mutation, Gene locus, Article, mental disorders, medicine, Humans, Copy-number variation, Protein Interaction Maps, Child, Exome sequencing, Priority journal, Risk assessment, Genetic association, Genetic risk, Genetics, Gene deletion, Copy number variation, General Neuroscience, Gene targeting, Genetic Variation, Genome project, medicine.disease, Synapse, Chromatin, Single nucleotide polymorphism, Gene structure, Intellectual impairment, Gene identification, Autism spectrum disorder, Genetic Loci, Female, Risk factor, Controlled study, Human
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). Through analysis of de novo mutations in autism spectrum disorder (ASD), Sanders et al. find that small deletions, but not large deletions/duplications, contain one critical gene. Combining CNV and sequencing data, they identify 6 loci and 65 genes associated with ASD.
Published: 2015
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21. Runs of homozygosity, copy number variation, and risk for depression and suicidal behavior in an Arab Bedouin kindred

Author: Abraham Weizman, Jamie Zelazny, Nadine M. Melhem, Sami Hamdan, Bernie Devlin, Amos Frisch, Danuta Wasserman, Elena Michaelovsky, Shawn Wood, Muhammad El-Heib, Miri Carmel, Ilana Farbstein, Alan Apter, Robert E. Ferrell, Lambertus Klei, and David A. Brent
Subjects: 0301 basic medicine, Adult, Male, Adolescent, DNA Copy Number Variations, Runs of Homozygosity, Biology, Article, Suicidal Ideation, 03 medical and health sciences, Consanguinity, Young Adult, 0302 clinical medicine, Risk Factors, Genetics, medicine, Ethnicity, Humans, Genetic Predisposition to Disease, Copy-number variation, Biological Psychiatry, Genetics (clinical), Depression (differential diagnoses), Suicide attempt, Depression, Homozygote, Reproducibility of Results, Odds ratio, Middle Aged, medicine.disease, Confidence interval, Arabs, Pedigree, Psychiatry and Mental health, 030104 developmental biology, Schizophrenia, Female, Inbreeding, 030217 neurology & neurosurgery
Abstract: OBJECTIVES Inbreeding increases the probability of homozygosity of deleterious alleles. Inbreeding and runs of homozygosity (ROH) are associated with an increased risk for disease phenotypes, including schizophrenia and other psychiatric disorders. The effects of inbreeding, ROH, homozygous deletions, and other copy number variations (CNVs) on risk for depression and suicide attempt (SA) were quantified in an Arab Bedouin Kindred. METHODS We carried out genetic analyses of 439 individuals from an Arab kindred with high rates of depression and suicidal behavior. We obtained complete ascertainment of SAs and first-degree relatives of individuals who have attempted or died by suicide. RESULTS We found extensive regions of ROH. On average, 5% of the genome is covered by ROH for these individuals, two-fold higher than ROH rates for individuals from populations of European ancestry. Inbreeding and total length of ROH were not associated with risk for depression or attempt. For CNVs, an increased number of duplications more than 500 kb was associated with an increased risk for attempt (odds ratio: 2.9; P=0.01; 95% confidence interval: 1.3-6.6). Although not significant after correction for multiple testing, the risk for SA appears to increase with copy number for a CNV on chromosome 9p24.1. This possibility is intriguing because the CNV covers GLDC, which encodes glycine dehydrogenase that binds to glycine, a co-agonist at N-methyl-D-aspartate glutamate receptors, and is involved in glutamatergic neurotransmission. CONCLUSION Our findings add to the growing evidence of genetic risk factors that act pleiotropically to increase the risk for several neuropsychiatric disorders, including depression and SA, irrespective of ancestry.
Published: 2017

22. Large-Scale Identification of Common Trait and Disease Variants Affecting Gene Expression

Author: Barbara K. Lipska, Mads E. Hauberg, Pamela Sklar, Hiroyoshi Toyoshiba, Oscar Franzén, Johan Björkegren, Laurent Essioux, Chang-Gyu Hahn, Panos Roussos, Raquel E. Gur, Bernie Devlin, Benjamin A. Logsdon, Timothy J. Vyse, Keisuke Hirai, David L. Morris, Vahram Haroutunian, Wen Zhang, Hardik Shah, Douglas M. Ruderfer, Solveig K. Sieberts, Arno Ruusalepp, Mette A. Peters, Kristen K. Dang, Joseph D. Buxbaum, Menachem Fromer, Thanneer M. Perumal, Milind Mahajan, Enrico Domenici, Lara M. Mangravite, David A. Lewis, Lambertus Klei, Jessica S. Johnson, Eric E. Schadt, and Claudia Giambartolomei
Subjects: 0301 basic medicine, Quantitative Trait Loci, LOCI, Genome-wide association study, Disease, Biology, Article, 03 medical and health sciences, Quantitative Trait, Heritable, Pleiotropy, TARGETS, Mendelian randomization, SCHIZOPHRENIA, Genetics, Humans, GWAS, Gene Regulatory Networks, Genetic Predisposition to Disease, POLYGENIC RISK, Gene, Genetics (clinical), Genetic association, EQTL, Correction, Genetic Variation, Genetic Pleiotropy, ASSOCIATION, Genetic architecture, 030104 developmental biology, Gene Expression Regulation, Expression quantitative trait loci, Schizophrenia, Educational Status, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWASs) have identified a multitude of genetic loci involved with traits and diseases. However, it is often unclear which genes are affected in such loci and whether the associated genetic variants lead to increased or decreased gene function. To mitigate this, we integrated associations of common genetic variants in 57 GWASs with 24 studies of expression quantitative trait loci (eQTLs) from a broad range of tissues by using a Mendelian randomization approach. We discovered a total of 3,484 instances of gene-trait-associated changes in expression at a false-discovery rate
Published: 2017

23. Limited contribution of rare, noncoding variation to autism spectrum disorder from sequencing of 2,076 genomes in quartet families

Author: Kathryn Roeder, Stephen Sanders, Joseph T. Glessner, Louw Smith, Neale Bm, Seva Kashin, Arnold R. Kriegstein, Bernie Devlin, Steven A. McCarroll, Tomasz J. Nowakowski, Benjamin Currall, Matthew W. State, Ryan M. Layer, Sirisha Pochareddy, Robert E. Handsaker, Eiriene-Chloe Markenscoff-Papadimitriou, Joseph D. Buxbaum, Shan Dong, Andrew Farrell, Jeffrey D. Mandell, Yuwen Liu, Xin He, Lambertus Klei, Lingxue Zhu, Grace Schwartz, Mark J. Daly, Joon Yong An, Michael C. Gilson, Harold Z. Wang, Mathew J Waterman, Michael E. Talkowski, Matthew R. Stone, Gabor T. Marth, Hilary Coon, A. Jeremy Willsey, Harrison Brand, Jeanselle Dea, Donna M. Werling, Ryan L. Collins, Clif Duhn, Nenad Sestan, John L.R. Rubenstein, Michael F. Walker, Carolyn A. Erdman, and Aaron R. Quinlan
Subjects: Whole genome sequencing, Genetics, 0303 health sciences, Genomics, Biology, medicine.disease, Genome, Structural variation, 03 medical and health sciences, 0302 clinical medicine, Variation (linguistics), Autism spectrum disorder, medicine, Coding region, Missense mutation, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: SummaryGenomic studies to date in autism spectrum disorder (ASD) have largely focused on newly arising mutations that disrupt protein coding sequence and strongly influence risk. We evaluate the contribution of noncoding regulatory variation across the size and frequency spectrum through whole genome sequencing of 519 ASD cases, their unaffected sibling controls, and parents. Cases carry a small excess of de novo (1.02-fold) noncoding variants, which is not significant after correcting for paternal age. Assessing 51,801 regulatory classes, no category is significantly associated with ASD after correction for multiple testing. The strongest signals are observed in coding regions, including structural variation not detected by previous technologies and missense variation. While rare noncoding variation likely contributes to risk in neurodevelopmental disorders, no category of variation has impact equivalent to loss-of-function mutations. Average effect sizes are likely to be smaller than that for coding variation, requiring substantially larger samples to quantify this risk.
Published: 2017
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24. Synaptic, transcriptional, and chromatin genes disrupted in autism

Author: Christine Stevens, Michael E. Zwick, Deepthi Rajagopalan, Mara Parellada, David J. Cutler, Li-San Wang, Norio Ozaki, Jinlu Cai, Lauren A. Weiss, Patricia Jiménez González, Jeffrey C. Barrett, Silvia De Rubeis, Helena Kilpinen, Alexander Kolevzon, Timothy W. Yu, Michael John Owen, Geraldine Dawson, Martin Schulte-Rüther, Jeremy R. Parr, Aarno Palotie, Eftichia Duketis, Lambertus Klei, Irene Lee, Bridget A. Fernandez, Aniko Sabo, Matthew W. State, Sarah Curran, Lucy Crooks, Chad M. Schafer, Avi Ma'ayan, Stephen Sanders, Evan T. Geller, Monica Biscaldi, Stephen W. Scherer, Christopher S. Poultney, Mark J. Daly, Patrick Bolton, Kaija Puura, Maria H. Chahrour, Michael Gill, Li Liu, Louise Gallagher, Ryan K. C. Yuen, Jack A. Kosmicki, Abraham Reichenberg, Christine M. Freitag, Shaun Purcell, Andreas G. Chiocchetti, Peter Szatmari, Sabine M. Klauck, Shih-Chen Fu, Christian R. Marshall, Joseph D. Buxbaum, Tarjinder Singh, Bernie Devlin, Chiao-Feng Lin, A. Ercument Cicek, Karola Rehnström, Pamela Sklar, Otto Valladares, Michael Sachse, Terho Lehtimäki, R. Sean Hill, Arthur P. Goldberg, A. Jeremy Willsey, Jing Lei, Branko Aleksic, Menachem Fromer, Yan Kou, Jessica M. Brownfeld, Annette Voran, Kathryn Roeder, Gerard D. Schellenberg, David Skuse, Thomas Lehner, Hilary Coon, Benjamin M. Neale, Iuliana Ionita-Laza, Kristiina Tammimies, Stephen J. Guter, Christopher A. Walsh, James S. Sutcliffe, Xin-Xin He, Alison L. McInnes, Emily L. Crawford, Nicholas G. Campbell, Angel Carracedo, R. Susan Walker, Edwin H. Cook, Kaitlin E. Samocha, and Christina M. Hultman
Subjects: Male, Transcription, Genetic, Molecular Sequence Data, Mutation, Missense, SYNGAP1, Article, 03 medical and health sciences, 0302 clinical medicine, Transcriptional regulation, Odds Ratio, Humans, Exome, Genetic Predisposition to Disease, Amino Acid Sequence, Gene, Exome sequencing, Germ-Line Mutation, 030304 developmental biology, Regulation of gene expression, Genetics, 0303 health sciences, Multidisciplinary, biology, Chromatin Assembly and Disassembly, Chromatin, Histone, Child Development Disorders, Pervasive, Mutation, Synapses, biology.protein, Female, Nerve Net, 030217 neurology & neurosurgery
Abstract: The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.
Published: 2014

25. Most genetic risk for autism resides with common variation

Author: Jennifer Reichert, Dina Manaa, Ann B. Lee, Stephan Ripke, Kathryn Roeder, Stephen Sanders, Pamela Sklar, Yudi Pawitan, Arthur P. Goldberg, Lambertus Klei, Corneliu A. Bodea, Christina M. Hultman, Bernie Devlin, Trent Gaugler, Joseph D. Buxbaum, Abraham Reichenberg, Sven Sandin, Milind Mahajan, and Oscar Svantesson
Subjects: Genetics, Extramural, Biology, Heritability, medicine.disease, Genetic architecture, Article, Variation (linguistics), mental disorders, medicine, Autism, Heritability of autism, Genetic risk, Allele
Abstract: A key component of genetic architecture is the allelic spectrum influencing trait variability. For autism spectrum disorder (henceforth autism) the nature of its allelic spectrum is uncertain. Individual risk genes have been identified from rare variation, especially de novo mutations1–8. From this evidence one might conclude that rare variation dominates its allelic spectrum, yet recent studies show that common variation, individually of small effect, has substantial impact en masse9,10. At issue is how much of an impact relative to rare variation. Using a unique epidemiological sample from Sweden, novel methods that distinguish total narrow-sense heritability from that due to common variation, and by synthesizing results from other studies, we reach several conclusions about autism’s genetic architecture: its narrow-sense heritability is ≈54% and most traces to common variation; rare de novo mutations contribute substantially to individuals’ liability; still their contribution to variance in liability, 2.6%, is modest compared to heritable variation.
Published: 2014

26. Transcriptional Consequences of 16p11.2 Deletion and Duplication in Mouse Cortex and Multiplex Autism Families

Author: Ian Blumenthal, Bernie Devlin, Joshua Z. Levin, Carl Ernst, Vanessa C. Wheeler, Ashok Ragavendran, Kathryn Roeder, Poornima Manavalan, Aarathi Sugathan, Serkan Erdin, Michael E. Talkowski, Lambertus Klei, James F. Gusella, Jolene R. Guide, and Julian Q. Zhou
Subjects: Male, DNA Copy Number Variations, Genotype, Transcription, Genetic, genetic structures, Genome-wide association study, Biology, Article, MECP2, Mice, 03 medical and health sciences, EHMT1, 0302 clinical medicine, Intellectual Disability, Chromosome Duplication, Gene duplication, Genetics, Animals, Humans, Genetics(clinical), Autistic Disorder, Child, Gene, Genetics (clinical), 030304 developmental biology, Cerebral Cortex, 0303 health sciences, Dosage compensation, Sequence Analysis, RNA, FMR1, Phenotype, Pedigree, Female, Chromosome Deletion, Chromosomes, Human, Pair 16, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Reciprocal copy-number variation (CNV) of a 593 kb region of 16p11.2 is a common genetic cause of autism spectrum disorder (ASD), yet it is not completely penetrant and can manifest in a wide array of phenotypes. To explore its molecular consequences, we performed RNA sequencing of cerebral cortex from mouse models with CNV of the syntenic 7qF3 region and lymphoblast lines from 34 members of 7 multiplex ASD-affected families harboring the 16p11.2 CNV. Expression of all genes in the CNV region correlated well with their DNA copy number, with no evidence of dosage compensation. We observed effects on gene expression outside the CNV region, including apparent positional effects in cis and in trans at genomic segments with evidence of physical interaction in Hi-C chromosome conformation data. One of the most significant positional effects was telomeric to the 16p11.2 CNV and includes the previously described "distal" 16p11.2 microdeletion. Overall, 16p11.2 CNV was associated with altered expression of genes and networks that converge on multiple hypotheses of ASD pathogenesis, including synaptic function (e.g., NRXN1, NRXN3), chromatin modification (e.g., CHD8, EHMT1, MECP2), transcriptional regulation (e.g., TCF4, SATB2), and intellectual disability (e.g., FMR1, CEP290). However, there were differences between tissues and species, with the strongest effects being consistently within the CNV region itself. Our analyses suggest that through a combination of indirect regulatory effects and direct effects on nuclear architecture, alteration of 16p11.2 genes disrupts expression networks that involve other genes and pathways known to contribute to ASD, suggesting an overlap in mechanisms of pathogenesis.
Published: 2014

27. Modest Impact on Risk for Autism Spectrum Disorder of Rare Copy Number Variants at 15q11.2, Specifically Breakpoints 1 to 2

Author: David H. Ledbetter, Timothy W. Yu, Matthew W. State, Christopher A. Walsh, James S. Sutcliffe, Michael T. Murtha, Dorothy E. Grice, Edwin H. Cook, Lambertus Klei, Daniel Moreno-De-Luca, Pauline Chaste, Bernie Devlin, Shrikant Mane, Donna M. Martin, Arthur L. Beaudet, A. Jeremy Willsey, Soo Jeong Kim, Daniel H. Geschwind, Jennifer K. Lowe, Kommu N. Mohan, Stephen Sanders, Catherine Lord, Eric M. Morrow, Youeun Song, Eric Fombonne, Vanessa Hus, and Christa Lese Martin
Subjects: Proband, Genetics, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, endocrine system diseases, General Neuroscience, Transmission disequilibrium test, Biology, medicine.disease, behavioral disciplines and activities, Penetrance, Chromosome 15, Autism spectrum disorder, mental disorders, medicine, Autism, Medical genetics, Neurology (clinical), Copy-number variation, Genetics (clinical)
Abstract: The proximal region of chromosome 15 is one of the genomic hotspots for copy number variants (CNVs). Among the rearrangements observed in this region, CNVs from the interval between the common breakpoints 1 and 2 (BP1 and BP2) have been reported cosegregating with autism spectrum disorder (ASD). Although evidence supporting an association between BP1-BP2 CNVs and autism accumulates, the magnitude of the effect of BP1-BP2 CNVs remains elusive, posing a great challenge to recurrence-risk counseling. To gain further insight into their pathogenicity for ASD, we estimated the penetrance of the BP1-BP2 CNVs for ASD as well as their effects on ASD-related phenotypes in a well-characterized ASD sample (n = 2525 families). Transmission disequilibrium test revealed significant preferential transmission only for the duplicated chromosome in probands (20T:9NT). The penetrance of the BP1-BP2 CNVs for ASD was low, conferring additional risks of 0.3% (deletion) and 0.8% (duplication). Stepwise regression analyses suggest a greater effect of the CNVs on ASD-related phenotype in males and when maternally inherited. Taken together, the results are consistent with BP1-BP2 CNVs as risk factors for autism. However, their effect is modest, more akin to that seen for common variants. To be consistent with the current American College of Medical Genetics guidelines for interpretation of postnatal CNV, the BP1-BP2 deletion and duplication CNVs would probably best be classified as variants of uncertain significance (VOUS): they appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status.
Published: 2014

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

Author: Joana Almeida, Christian R. Marshall, Hakon Hakonarson, Bárbara Oliveira, Anthony J. Griswold, Jacob A. S. Vorstman, Bhooma Thiruvahindrapuram, Suma Jacob, Judith Conroy, Alistair T. Pagnamenta, Christelle Cabrol, Jeremy R. Parr, Daniel H. Geschwind, Nancy J. Minshew, Xiao Xu, Richard Anney, Sven Bölte, Zhuozhi Wang, Emily L. Crawford, Elsa Delaby, Margaret A. Pericak-Vance, Joachim Hallmayer, Jonathan L. Haines, Dalila Pinto, Susana Mouga, Alexander Kolevzon, Elena Bacchelli, Frederico Duque, Bernie Devlin, Latha Soorya, Cátia Café, Kirsty Wing, Jennifer K. Lowe, Ana Tryfon, Stephen J. Guter, Geraldine Dawson, Tiago R. Magalhaes, Anthony J. Bailey, Michael Gill, Peter Szatmari, Steven Gallinger, Marion Pilorge, James S. Sutcliffe, Bridget A. Fernandez, Herman van Engeland, Catalina Betancur, Guiomar Oliveira, Andrew Green, Eftichia Duketis, Bernadette Rogé, Ann Le Couteur, Evdokia Anagnostou, Michelle Cotterchio, Daniele Merico, Giovanna Pellecchia, Jonathan Green, Regina Regan, Jillian P. Casey, Guiqing Cai, Gerard D. Schellenberg, Jennifer L. Howe, Elena Maestrini, Andrew D. Paterson, L. Alison McInnes, Patrick Bolton, Edwin H. Cook, Richard Delorme, Lambertus Klei, Thomas Bourgeron, Gillian Baird, Christine M. Freitag, Beth A. Dombroski, Andreas G. Chiocchetti, Sabine M. Klauck, Susan E. Folstein, Mafalda Barbosa, Anthony P. Monaco, Marion Leboyer, Nadia Bolshakova, Fritz Poustka, Richard Holt, Kerstin Wittemeyer, Wendy Roberts, Lonnie Zwaigenbaum, Louise Gallagher, Susan G. McGrew, Joseph D. Buxbaum, Graham Casey, Simon Wallace, Catherine Lord, Sean Brennan, Robert Ziman, Alison K. Merikangas, John I. Nurnberger, Christopher Gillberg, Ellen M. Wijsman, Astrid M. Vicente, Inȇs C. Conceição, Sean Ennis, Patricia Jiménez González, Hilary Coon, Raphael Bernier, John R. Gilbert, Ann P. Thompson, Susanne Thomson, Agatino Battaglia, Maretha de Jonge, Michael L. Cuccaro, Catarina Correia, Veronica J. Vieland, Stephen W. Scherer, Pauline Chaste, Departments of Psychiatry, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Seaver Autism Center-, The Mindich Child Health & Development Institute, Department of Psychiatry, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Seaver Autism Center for Research and Treatment, Friedman Brain Institute, The Mindich Child Health and Development Institute, The Icahn Institute for Genomics and Multiscale Biology, Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Trinity College Dublin-St. James's Hospital, Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario]-Offord Centre for Child Studies, Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), McLaughlin Centre, University of Toronto, BioFIG, Center for Biodiversity, Functional and Integrative Genomics, Department of Neurology, University of California [Los Angeles] (UCLA), University of California-University of California-David Geffen School of Medicine [Los Angeles], University of California-University of California, Fisico-Quimica Biologica, Universidade Federal do Rio de Janeiro (UFRJ), John P. Hussman Institute for Human Genomics, University of Miami [Coral Gables], Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Pathology and Laboratory Medicine, University of Pennsylvania [Philadelphia], Department of Pathology, Vanderbilt Brain Institute, Vanderbilt University School of Medicine [Nashville], Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University [Nashville]-Centers for Human Genetics Research and Molecular Neuroscience, Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital [Toronto, Canada] (MSH), Prevention & Cancer Control, Cancer Care Ontario, Department of Preventive Medicine, University of Southern California (USC), Department of Pediatrics, University of Alberta, School of Education, University of Birmingham [Birmingham], University of Oxford [Oxford]-Warneford Hospital, Octogone Unité de Recherche Interdisciplinaire (Octogone), Université Toulouse - Jean Jaurès (UT2J), Autism Research Unit, The Hospital for sick children [Toronto] (SickKids)-University of Toronto, Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Institute for Biomedical Imaging and Life Science, University of Coimbra [Portugal] (UC), Vanderbilt University [Nashville], Center for Autism and the Developing Brain (CADB), Weill Medical College of Cornell University [New York], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Institute of Health and Society, Newcastle University [Newcastle], Department of Child and Adolescent Psychiatry, Newcastle University [Newcastle]-Institute of Health & Society (Child & Adolescent Psychiatry), Child Developmental and Behavioral Unit, Hospital Nacional de Niños Dr Sáenz Herrera, Institute for Juvenile Research-University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Manchester Academic Health Sciences Centre, Gillberg Neuropsychiatry Centre [Göteborg, Sueden], Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg (GU), Institute of Child Health, University College of London [London] (UCL), Memorial University of Newfoundland [St. John's], Disciplines of Genetics and Medicine, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Institute of Psychiatry, King‘s College London, Institute of psychiatry, University of Washington [Seattle], Paediatric Neurodisability, King‘s College London-King's Health Partners, MRC Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London-The Institute of Psychiatry, University of British Columbia (UBC), Bloorview Research Institute, Division of Medical Genetics [Seattle], Departments of Biostatistics and Medicine, Battelle Center for Mathematical Medicine, Ohio State University [Columbus] (OSU)-Nationwide Children's Hospital, Institute of Neuroscience [Newcastle] (ION), Institutes of Neuroscience and Health and Society, Indiana University School of Medicine, Indiana University System-Indiana University System, The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Children’s Hospital of Philadelphia (CHOP ), Utah Autism Research Program, University of Utah Psychiatry Department, University of Miami School of Medicine, Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris [Pisa], Department of Psychiatry and Behavioral Sciences [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford School of Medicine [Stanford], Institute for Juvenile Research, University of Illinois [Chicago] (UIC), Department of Neuroscience, Main funders of the Autism Genome Project: Autism Speaks (USA), the Health Research Board (Ireland, AUT/2006/1, AUT/2006/2, PD/2006/48), the Medical Research Council (UK), the Hilibrand Foundation (USA), Genome Canada, the Ontario Genomics Institute, and the Canadian Institutes of Health Research (CIHR), Autism Genome Project Consortium, Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Oxford, University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], University of California (UC)-University of California (UC), University of Pennsylvania, University of Oxford-Warneford Hospital, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania-University of Pennsylvania-Children’s Hospital of Philadelphia (CHOP ), Betancur, Catalina, Instituto Nacional de Saude Dr Ricardo Jorge, Universidade Federal do Rio de Janeiro [Rio de Janeiro] (UFRJ), Laboratoire Analyse et Modélisation pour la Biologie et l'Environnement (LAMBE - UMR 8587), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Università di Bologna [Bologna] (UNIBO), Mount Sinai Hospital (MSH), University of Toronto-The Hospital for Sick Children, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Gillberg Neuropsychiatry Centre, University of Gothenburg (GU), Stanford University Medical School, Stanford University School of Medicine [Stanford], Stanford University [Stanford], Université de Toulouse (UT)-Université de Toulouse (UT), Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, Thiruvahindrapuram B, Xu X, Ziman R, Wang Z, Vorstman JA, Thompson A, Regan R, Pilorge M, Pellecchia G, Pagnamenta AT, Oliveira B, Marshall CR, Magalhaes TR, Lowe JK, Howe JL, Griswold AJ, Gilbert J, Duketis E, Dombroski BA, De Jonge MV, Cuccaro M, Crawford EL, Correia CT, Conroy J, Conceição IC, Chiocchetti AG, Casey JP, Cai G, Cabrol C, Bolshakova N, Bacchelli E, Anney R, Gallinger S, Cotterchio M, Casey G, Zwaigenbaum L, Wittemeyer K, Wing K, Wallace S, van Engeland H, Tryfon A, Thomson S, Soorya L, Rogé B, Roberts W, Poustka F, Mouga S, Minshew N, McInnes LA, McGrew SG, Lord C, Leboyer M, Le Couteur AS, Kolevzon A, Jiménez González P, Jacob S, Holt R, Guter S, Green J, Green A, Gillberg C, Fernandez BA, Duque F, Delorme R, Dawson G, Chaste P, Café C, Brennan S, Bourgeron T, Bolton PF, Bölte S, Bernier R, Baird G, Bailey AJ, Anagnostou E, Almeida J, Wijsman EM, Vieland VJ, Vicente AM, Schellenberg GD, Pericak-Vance M, Paterson AD, Parr JR, Oliveira G, Nurnberger JI, Monaco AP, Maestrini E, Klauck SM, Hakonarson H, Haines JL, Geschwind DH, Freitag CM, Folstein SE, Ennis S, Coon H, Battaglia A, Szatmari P, Sutcliffe JS, Hallmayer J, Gill M, Cook EH, Buxbaum JD, Devlin B, Gallagher L, Betancur C, and Scherer SW.
Subjects: Male, INTELLECTUAL DISABILITY, pathways, Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, Bioinformatics, DUPLICATIONS, Intellectual disability, Gene Regulatory Networks, Genetics(clinical), Copy-number variation, 10. No inequality, Child, GDI1, Genetics (clinical), Sequence Deletion, COPY NUMBER VARIANTS, Genetics, gene networks, Copy Number Variation, 3. Good health, Pedigree, Fragile X syndrome, Multigene Family, Female, Metabolic Networks and Pathways, de novo, DNA Copy Number Variations, autism, Biology, rare CNV, PHENOTYPE ONTOLOGY, Article, Structural variation, mental disorders, medicine, Humans, ddc:610, FRAGILE-X-SYNDROME, GENOME-WIDE ASSOCIATION, Gene, [SDV.GEN]Life Sciences [q-bio]/Genetics, HDAC4, SETD5, medicine.disease, CHD2, inherited, STRUCTURAL VARIATION, DELETIONS, DE-NOVO MUTATIONS, Child Development Disorders, Pervasive, Autism
Abstract: International audience; Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
Published: 2014
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29. 5.45 RECURRENT AND LARGE COPY NUMBER VARIATION IN OCD RISK: RESULTS FROM THE EGOS STUDY

Author: Christina M. Hultman, Bernie Devlin, Lambertus Klei, Dorothy E. Grice, Behrang Mahjani, Joseph D. Buxbaum, Silvia De Rubeis, Maureen Mulhern, Xinyi Xu, and Sven Sandin
Subjects: Genetics, Psychiatry and Mental health, Developmental and Educational Psychology, Copy-number variation, Biology
Published: 2019

30. A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition

Author: Raquel Milgrom, Yashoda Sharma, Leif Törkvist, Mauro D'Amato, Talin Haritunians, Ramnik J. Xavier, Hakon Hakonarson, Leonard Baidoo, Ashwin N. Ananthakrishnan, Marla Dubinsky, Graham L. Radford-Smith, Deborah D. Proctor, Mark J. Daly, Subra Kugathasan, Jan Hendrik Niess, Judy H. Cho, Jürgen Glas, L. Philip Schumm, Mark S. Silverberg, Claudio Fiocchi, Lambertus Klei, Ken Y. Hui, Miguel Regueiro, James Borneman, Dalin Li, Jonathan Braun, Steven R. Brant, Dermot P.B. McGovern, John D. Rioux, Stephan Brand, Jonas Halfvarson, Guy Aumais, Jean Paul Achkar, Lisa A. Simms, Carsten Büning, Joanne M. Stempak, Stephan R. Targan, Jonathan P. Jacobs, Richard H. Duerr, and Bernie Devlin
Subjects: 0301 basic medicine, Male, Linkage disequilibrium, Genome-wide association study, Ulcerative, Crohn's Disease, Inflammatory bowel disease, Oral and gastrointestinal, Crohn Disease, Polymorphism (computer science), Risk Factors, 2.1 Biological and endogenous factors, Aetiology, Cation Transport Proteins, Genetics, Microbiota, Gastroenterology, Genetic Pleiotropy, Colitis, Female, Genotype, Clinical Sciences, Mutation, Missense, Single-nucleotide polymorphism, Biology, Autoimmune Disease, Article, Paediatrics and Reproductive Medicine, 03 medical and health sciences, Clinical Research, medicine, Humans, Microbiome, Allele, Alleles, Genetic association, Nutrition, Hepatology, Gastroenterology & Hepatology, Inflammatory Bowel Disease, Human Genome, Neurosciences, medicine.disease, Inflammatory Bowel Diseases, Gastrointestinal Microbiome, 030104 developmental biology, Case-Control Studies, Mutation, Colitis, Ulcerative, Missense, Digestive Diseases
Abstract: Background & aimsGenome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA).MethodsGenotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing.ResultsWe identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P= 5.55× 10(-13)). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P= .009) and CD cases(P= .0009). Moreover, microbes depleted in healthycarriers strongly overlap with those reduced in CD patients (P=9.24× 10(-16)) and overweight individuals (P=6.73×10(-16)).ConclusionsOur results suggest that anSLC39A8-dependent shift in the gut microbiome could explain itspleiotropic effects on multiple complex diseases includingCD.
Published: 2016

31. Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia

Author: Keisuke Hirai, Joseph D. Buxbaum, Robin Kramer, Li Xie, Kristen K. Dang, Kathryn Roeder, Towfique Raj, Barbara K. Lipska, Shaun Purcell, Lambertus Klei, Panos Roussos, John F. Fullard, Vahram Haroutonian, A. Ercument Cicek, Konrad Talbot, Raquel E. Gur, Solveig K. Sieberts, Scott E. Hemby, Leslie A. Shinobu, Jun Zhu, Mette A. Peters, Pamela Sklar, Kristen J. Brennand, Aaron Topol, David A. Lewis, Mahsa Parvisi, Chang-Gyu Hahn, Ying-Chih Wang, Menachem Fromer, Nicholas Katsanis, Jessica S. Johnson, David A. Bennett, Andrew W. Browne, Zeynep H. Gümüş, Jonathan M. J. Derry, Ben Readhead, Edwin C. Oh, Benjamin A. Logsdon, Dalila Pinto, Cong Lu, David H. Kavanagh, Eli A. Stahl, Lara M. Mangravite, Enrico Domenici, Thanneer M. Perumal, Milind Mahajan, Douglas M. Ruderfer, Philip L. De Jager, Patrick F. Sullivan, Hiroyoshi Toyoshiba, Hardik Shah, Andrew Chess, Bin Zhang, Bernie Devlin, Joel T. Dudley, Tymor Hamamsy, and Eric E. Schadt
Subjects: Genetics, 0303 health sciences, biology, Genomics, biology.organism_classification, medicine.disease, Small hairpin RNA, 03 medical and health sciences, 0302 clinical medicine, Schizophrenia, Genetic variation, Gene expression, biology.protein, medicine, Zebrafish, Furin, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Over 100 genetic loci harbor schizophrenia associated variants, yet how these common variants confer risk is uncertain. The CommonMind Consortium has sequenced dorsolateral prefrontal cortex RNA from schizophrenia cases (n=258) and control subjects (n=279), creating the largest publicly available resource to date of gene expression and its genetic regulation; ∼5 times larger than the latest release of GTEx. Using this resource, we find that ∼20% of the schizophrenia risk loci have common variants that could explain regulation of brain gene expression. In five loci, these variants modulate expression of a single gene: FURIN, TSNARE1, CNTN4, CLCN3 or SNAP91. Experimentally altered expression of three of them, FURIN, TSNARE1, and CNTN4, perturbs the proliferation and apoptotic index of neural progenitors and leads to neuroanatomical deficits in zebrafish. Furthermore, shRNA mediated knock-down of FURIN1 in neural progenitor cells derived from human induced pluripotent stem cells produces abnormal neural migration. Although 4.2% of genes (N = 693) display significant differential expression between cases and controls, 44% show some evidence for differential expression. All fold changes are ≤ 1.33, and an independent cohort yields similar differential expression for these 693 genes (r = 0.58). These findings are consistent with schizophrenia being highly polygenic, as has been reported in investigations of common and rare genetic variation. Co-expression analyses identify a gene module that shows enrichment for genetic associations and is thus relevant for schizophrenia. Taken together, these results pave the way for mechanistic interpretations of genetic liability for schizophrenia and other brain diseases.
Published: 2016

32. Gene expression elucidates functional impact of polygenic risk for schizophrenia

Author: David A. Lewis, Lara M. Mangravite, Bernie Devlin, Hardik Shah, Andrew Chess, Keisuke Hirai, Ben Readhead, Patrick F. Sullivan, Kathryn Roeder, Robin Kramer, Chang-Gyu Hahn, Shaun Purcell, Mahsa Parvisi, Cong Lu, Nicholas Katsanis, Edwin C. Oh, Douglas M. Ruderfer, Solveig K. Sieberts, David H. Kavanagh, Thanneer M. Perumal, Eli A. Stahl, Jessica S. Johnson, Mette A. Peters, Milind Mahajan, Panos Roussos, Menachem Fromer, David A. Bennett, Hiroyoshi Toyoshiba, Kristen K. Dang, Lambertus Klei, Tymor Hamamsy, Philip L. De Jager, Joseph D. Buxbaum, Jianqiu Xiao, Vahram Haroutunian, Barbara K. Lipska, Jun Zhu, Jonathan M. J. Derry, Kristen J. Brennand, A. Ercument Cicek, Ying-Chih Wang, Benjamin A. Logsdon, Dalila Pinto, Andrew W. Browne, Konrad Talbot, Eric E. Schadt, Scott E. Hemby, Bin Zhang, Raquel E. Gur, Leslie A. Shinobu, Towfique Raj, Joel T. Dudley, Enrico Domenici, Pamela Sklar, John F. Fullard, Zeynep H. Gümüş, Lu Xie, and Aaron Topol
Subjects: 0301 basic medicine, Male, Risk, Multifactorial Inheritance, Genomics, Genome-wide association study, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Gene expression, Humans, Genetic Predisposition to Disease, Gene, Furin, Genetics, Regulation of gene expression, Gene knockdown, Neuroscience (all), biology, General Neuroscience, Brain, 030104 developmental biology, Gene Expression Regulation, Expression quantitative trait loci, biology.protein, Schizophrenia, Female, Neuroscience, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Over 100 genetic loci harbor schizophrenia-associated variants, yet how these variants confer liability is uncertain. The CommonMind Consortium sequenced RNA from dorsolateral prefrontal cortex of people with schizophrenia (N = 258) and control subjects (N = 279), creating a resource of gene expression and its genetic regulation. Using this resource, ∼20% of schizophrenia loci have variants that could contribute to altered gene expression and liability. In five loci, only a single gene was involved: FURIN, TSNARE1, CNTN4, CLCN3 or SNAP91. Altering expression of FURIN, TSNARE1 or CNTN4 changed neurodevelopment in zebrafish; knockdown of FURIN in human neural progenitor cells yielded abnormal migration. Of 693 genes showing significant case-versus-control differential expression, their fold changes were ≤ 1.33, and an independent cohort yielded similar results. Gene co-expression implicates a network relevant for schizophrenia. Our findings show that schizophrenia is polygenic and highlight the utility of this resource for mechanistic interpretations of genetic liability for brain diseases.
Published: 2016
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33. Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis

Author: Marla Gearing, David G. Clark, Steven L. Carroll, Marianne Johnstone, Darwin L. Conwell, Gregory A. Cote, Sandra Weintraub, Matthew P. Frosch, Stuart Sherman, Badri N. Vardarajan, Joshua A. Sonnen, Lindy E. Harrell, Peter B. Cotton, Lisa L. Barnes, Lawrence S. Honig, Carol A. Miller, Adam Slivka, Michelle A. Anderson, Nadine M. Melhem, David A. Bennett, Joel H. Kramer, Jill P. Smith, Michele D. Lewis, Mary Ganguli, Jean Paul Vonsatte, Thomas J. Montine, Lee-Way Jin, Kenneth B. Fallon, Marilyn S. Albert, Eliezer Masliah, John H. Growdon, Barry Reisberg, Chuanhai Cao, Patricia L. Kramer, Douglas J. Hartman, Allan I. Levey, Jennifer Williamson, Vivianna M. Van Deerlin, Wayne W. Poon, Alison Goate, Vijay P. Singh, Bernie Devlin, Christiane Reitz, Ann C. McKee, Amanda Smith, Neill R. Graff-Radford, Walter A. Kukul, John Baillie, Andres Gelrud, Ranjan Duara, Thomas D. Bird, Clinton B. Wright, Deborah Blacker, Chiao-Feng Lin, Ge Li, Ronald C. Kim, Deborah C. Mash, Debby W. Tsuang, John P. Neoptolemos, Timothy B. Gardner, Kathryn L. Lunetta, Steven G. Younkin, Kara L. Hamilton-Nelson, Ronald L. Hamilton, F. Yesim Demirci, Eric M. Reiman, Charles DeCarli, John M Olichney, Richard Mayeux, Gregory A. Jicha, Michael R. O'Connell, Matt Tector, Eileen H. Bigio, Jonathan D. Glass, M. Ilyas Kamboh, Randall E. Brand, Christopher Lawrence, Steven E. Arnold, Jessica LaRusch, Elaine R. Peskind, David H. Cribbs, M.-Marsel Mesulam, Constantine G. Lyketsos, Michelle L. Kienholz, Frank M. LaFerla, Duane Beekly, Kelley Faber, Salvatore Spina, Gyungah Jun, Thiruvengadam Muniraj, Erik D. Roberson, Anna Karydas, Steven H. Ferris, Bruce L. Miller, Randall L. Woltjer, Li-San Wang, Lon S. Schneider, John C. Morris, John Q. Trojanowski, Jeffrey Kaye, Joseph E. Parisi, Nilufer Ertekin-Taner, Harry V. Vinters, Lidiya Orlichenko, Robert Barber, Chris E. Forsmark, Mary Sano, Bimaljit S. Sandhu, Peter A. Banks, Martin R. Farlow, Bradley T. Hyman, Joseph F. Quinn, Gary W. Beecham, James A. DiSario, Hakon Hakonarson, Daniel C. Marson, Adam C. Naj, Frank Martiniuk, Oscar L. Lopez, Mary E. Money, Julia Mayerle, William Greenhalf, Kathryn Roeder, Adam L. Boxer, Christine M. Hulette, Gerard D. Schellenberg, Georgios I. Papachristou, Douglas Galasko, James R. Burke, Donna B. Stolz, Murray A. Raskind, Peter Simon, Linda J. Van Eldik, Robert A. Hawes, Chang En Yu, Tatiana Foroud, Jonathan L. Haines, Stephen R. Wisniewski, William W. Seeley, Dhiraj Yadav, James J. Lah, C. Mel Wilcox, Sid Gilman, Liana G. Apostolova, Howard J. Rosen, Clinton T. Baldwin, Robert S. Stern, Narcis O. Zarnescu, Dennis W. Dickson, Margaret A. Pericak-Vance, Ashok Raj, Stephen T. Amann, Joseph D. Buxbaum, Ronald C. Petersen, Robert C. Green, David C. Whitcomb, Rudolph E. Tanzi, Lindsay A. Farrer, Helena C. Chui, Laura B. Cantwell, Wendy J. Mack, Samer Alkaade, Nigel J. Cairns, Thomas G. Beach, Frank Ulrich Weiss, Alyssa M. Krasinskas, Elizabeth Head, Nalini M. Guda, Julie A. Schneider, Malcolm B. Dick, Roger N. Rosenberg, Jill R. Murrel, Otto Valladares, Andrew J. Saykin, Huntington Potter, John R. Gilbert, Neil W. Kowall, Joseph Romagnuolo, Markus M. Lerch, Aimee Pierce, Roger L. Albin, John M. Ringman, James B. Leverenz, Carlos Cruchaga, Joshua W. Miller, Lei Yu, M. Michael Barmada, Lambertus Klei, Andrew P. Lieberman, Bernardino Ghetti, Robert Sutton, Kathleen A. Welsh-Bohmer, Juan C. Troncoso, Edward H. Koo, Elizabeth Crocco, Eden R. Martin, Daniel H. Geschwind, and Regina M. Carney
Subjects: Male, Pancreatic disease, Pancreatitis, Alcoholic, Genome-wide association study, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Sex Factors, Gene Frequency, Genotype, Genetics, medicine, PRSS2, Humans, Genetic Predisposition to Disease, Trypsin, Allele, Allele frequency, Homozygote, Genetic Variation, medicine.disease, 3. Good health, Hemizygote, 030220 oncology & carcinogenesis, Immunology, Claudins, Mutation, Trypsinogen, Pancreatitis, 030211 gastroenterology & hepatology, Female, Genome-Wide Association Study
Abstract: Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P < 1 × 10(-12)) and X-linked CLDN2 (P < 1 × 10(-21)) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07).
Published: 2012

34. Evaluation of HLA Polymorphisms in Relation to Schizophrenia Risk and Infectious Exposure

Author: Joseph Kwentus, Mikhil Bamne, Annie M. Watson, Rodney T. Perry, Lambertus Klei, Trina B. Allen, Alberto B. Santos, Joseph P. McEvoy, Henry A. Nasrallah, B. Devlin, Cemil Çelik, L. DiAnne Bradford, Raquel E. Gur, Joel Wood, Hader Mansour, Robert Savage, Neil B. Edwards, Monica E. Calkins, Rodney C.P. Go, Robert H. Yolken, Vishwajit L. Nimgaonkar, Ruben C. Gur, and Kodavali V. Chowdari
Subjects: Adult, Male, Genotype, Population, Cytomegalovirus, Genome-wide association study, Single-nucleotide polymorphism, Herpesvirus 1, Human, Human leukocyte antigen, Biology, Polymorphism, Single Nucleotide, HLA Antigens, Risk Factors, Polymorphism (computer science), Humans, Genetic Predisposition to Disease, Allele, education, Genetic association, Genetics, education.field_of_study, Butyrophilins, Membrane Proteins, Herpes Simplex, Invited Themed Article, Middle Aged, Black or African American, Psychiatry and Mental health, Case-Control Studies, Toxoplasmosis, Cerebral, Cytomegalovirus Infections, Multivariate Analysis, Immunology, Schizophrenia, Chromosomes, Human, Pair 6, Female
Abstract: Background: Genome-wide association studies (GWAS) implicate single nucleotide polymorphisms (SNPs) on chromosome 6p21.3-22.1, the human leukocyte antigen (HLA) region, as common risk factors for schizophrenia (SZ). Other studies implicate viral and protozoan exposure. Our study tests chromosome 6p SNPs for effects on SZ risk with and without exposure. Method: GWAS-significant SNPs and ancestry-informative marker SNPs were analyzed among African American patients with SZ (n = 604) and controls (n = 404). Exposure to herpes simplex virus, type 1 (HSV-1), cytomegalovirus (CMV), and Toxoplasma gondii (TOX) was assayed using specific antibody assays. Results: Five SNPs were nominally associated with SZ, adjusted for population admixture (P < .05, uncorrected for multiple comparisons). These SNPs were next analyzed in relation to infectious exposure. Multivariate analysis indicated significant association between rs3130297 genotype and HSV-1 exposure; the associated allele was different from the SZ risk allele. Conclusions: We propose a model for the genesis of SZ incorporating genomic variation in the HLA region and neurotropic viral exposure for testing in additional, independent African American samples.
Published: 2012

35. Genome-wide Transcriptome Profiling Reveals the Functional Impact of Rare De Novo and Recurrent CNVs in Autism Spectrum Disorders

Author: Stephen Sanders, Bernie Devlin, Su H. Chu, Rui Luo, Daniel H. Geschwind, Lambertus Klei, Ni Huang, Jennifer K. Lowe, Irina Voineagu, Chaochao Cai, Matthew E. Hurles, Jing Ou, Yuan Tian, and Matthew W. State
Subjects: Proband, Child Development Disorders, DNA Copy Number Variations, Intellectual and Developmental Disabilities (IDD), Autism, Biology, medicine.disease_cause, Medical and Health Sciences, Genome, Article, Chromosomes, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Gene expression, Genetics, medicine, Humans, 2.1 Biological and endogenous factors, Genetics(clinical), Aetiology, Child, Preschool, Gene, Genetics (clinical), Pervasive, 030304 developmental biology, Pediatric, Genetics & Heredity, 0303 health sciences, Mutation, Pair 16, Gene Expression Profiling, Human Genome, Neurosciences, Biological Sciences, medicine.disease, Phenotype, Brain Disorders, Mental Health, Child Development Disorders, Pervasive, Child, Preschool, Chromosomes, Human, Pair 16, 030217 neurology & neurosurgery, Human
Abstract: Copy-number variants (CNVs) are a major contributor to the pathophysiology of autism spectrum disorders (ASDs), but the functional impact of CNVs remains largely unexplored. Because brain tissue is not available from most samples, we interrogated gene expression in lymphoblasts from 244 families with discordant siblings in the Simons Simplex Collection in order to identify potentially pathogenic variation. Our results reveal that the overall frequency of significantly misexpressed genes (which we refer to here as outliers) identified in probands and unaffected siblings does not differ. However, in probands, but not their unaffected siblings, the group of outlier genes is significantly enriched in neural-related pathways, including neuropeptide signaling, synaptogenesis, and cell adhesion. We demonstrate that outlier genes cluster within the most pathogenic CNVs (rare de novo CNVs) and can be used for the prioritization of rare CNVs of potentially unknown significance. Several nonrecurrent CNVs with significant gene-expression alterations are identified (these include deletions in chromosomal regions 3q27, 3p13, and 3p26 and duplications at 2p15), suggesting that these are potential candidate ASD loci. In addition, we identify distinct expression changes in 16p11.2 microdeletions, 16p11.2 microduplications, and 7q11.23 duplications, and we show that specific genes within the 16p CNV interval correlate with differences in head circumference, an ASD-relevant phenotype. This study provides evidence that pathogenic structural variants have a functional impact via transcriptome alterations in ASDs at a genome-wide level and demonstrates the utility of integrating gene expression with mutation data for the prioritization of genes disrupted by potentially pathogenic mutations.
Published: 2012

36. Amino acid position 11 of HLA-DRβ1 is a major determinant of chromosome 6p association with ulcerative colitis

Author: Massimo Trucco, Lambertus Klei, Bernie Devlin, Richard H. Duerr, Aaron Brzezinski, Kathyrn Roeder, N. Rebert, Claudio Fiocchi, Gaia Bellone, Steven Ringquist, P. I W De Bakker, Jean-Paul Achkar, Kamboh Mi, Miguel Regueiro, Regan Scott, and Ying Lu
Subjects: Genotype, HLA-DR beta-Chains, Immunology, Locus (genetics), Genome-wide association study, Single-nucleotide polymorphism, Human leukocyte antigen, Major histocompatibility complex, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, Gene Frequency, Genetics, Humans, SNP, Genetic Predisposition to Disease, Allele frequency, Alleles, Genetics (clinical), ulcerative colitis, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, inflammatory bowel disease genetics, biology, major histocompatibility complex, Amino acid, Amino Acid Substitution, chemistry, biology.protein, Chromosomes, Human, Pair 6, Colitis, Ulcerative, 030211 gastroenterology & hepatology, Genome-Wide Association Study
Abstract: The major histocompatibility complex (MHC) on chromosome 6p is an established risk locus for ulcerative colitis (UC) and Crohn's disease (CD). We aimed to better define MHC association signals in UC and CD by combining data from dense single-nucleotide polymorphism (SNP) genotyping and from imputation of classical human leukocyte antigen (HLA) types, their constituent SNPs and corresponding amino acids in 562 UC, 611 CD and 1428 control subjects. Univariate and multivariate association analyses were performed, controlling for ancestry. In univariate analyses, absence of the rs9269955 C allele was strongly associated with risk for UC (P = 2.67 × 10(-13)). rs9269955 is a SNP in the codon for amino acid position 11 of HLA-DRβ1, located in the P6 pocket of the HLA-DR antigen binding cleft. This amino acid position was also the most significantly UC-associated amino acid in omnibus tests (P = 2.68 × 10(-13)). Multivariate modeling identified rs9269955-C and 13 other variants in best predicting UC vs control status. In contrast, there was only suggestive association evidence between the MHC and CD. Taken together, these data demonstrate that variation at HLA-DRβ1, amino acid 11 in the P6 pocket of the HLA-DR complex antigen binding cleft is a major determinant of chromosome 6p association with UC.
Published: 2011

37. Copy Number Variants for Schizophrenia and Related Psychotic Disorders in Oceanic Palau: Risk and Transmission in Extended Pedigrees

Author: Bernie Devlin, Kathryn Roeder, Nadine M. Melhem, Josepha Tiobech, Lambertus Klei, Frank A. Middleton, Stevenson Kuartei, William Byerley, Kathryn McFadden, Marina Myles-Worsley, Stephen V. Faraone, Sophia Vinogradov, and Victor Yano
Subjects: Genetics, education.field_of_study, Population, Case-control study, Pedigree chart, Odds ratio, Biology, medicine.disease, Schizophrenia, mental disorders, medicine, Copy-number variation, education, Allele frequency, Biological Psychiatry, SNP array
Abstract: Background We report on copy number variants (CNVs) found in Palauan subjects ascertained for schizophrenia and related psychotic disorders in extended pedigrees in Palau. We compare CNVs found in this Oceanic population with those seen in other samples, typically of European ancestry. Assessing CNVs in Palauan extended pedigrees yields insight into the evolution of risk CNVs, such as how they arise, are transmitted, and are lost from populations by stochastic or selective processes, none of which are easily measured from case-control samples. Methods DNA samples from 197 subjects affected with schizophrenia and related psychotic disorders, 185 of their relatives, and 159 control subjects were successfully characterized for CNVs using Affymetrix Genomewide Human SNP Array 5.0. Results Copy number variants thought to be associated with risk for schizophrenia and related disorders also occur in affected individuals in Palau, specifically 15q11.2 and 1q21.1 deletions, partial duplication of IL1RAPL1 (Xp21.3), and chromosome X duplications (Klinefelter's syndrome). Partial duplication within A2BP1 appears to convey an eightfold increased risk in male subjects (95% confidence interval, .8–84.4) but not female subjects (odds ratio=.4, 95% confidence interval, .03–4.9). Affected-only linkage analysis using this variant yields a logarithm of the odds score of 3.5. Conclusions This study reveals CNVs that confer risk to schizophrenia and related psychotic disorders in Palau, most of which have been previously observed in samples of European ancestry. Only a few of these CNVs show evidence that they have existed for many generations, consistent with risk variants diminishing reproductive success.
Published: 2011

38. Identification of common variants influencing risk of the tauopathy Progressive Supranuclear Palsy

Author: Marla Gearing, Jean Paul G. Vonsattel, Anna Karydas, Manuela Apfelbacher, Herbert Budka, Bernie Devlin, Alessandro Padovani, Wallace W. Tourtellotte, Andrew J. Lees, Karin Srulijes, Li-San Wang, Klaus Seppi, Gianni Pezzoli, Yvette Bordelon, Claudia Trenkwalder, Ryan J. Uitti, Peter Paul De Deyn, Nicole A. Finch, Roger L. Albin, Ranjan Duara, Gerard D. Schellenberg, Alberto Rábano, Kelly E. Lyons, Rosa Rademakers, Douglas Galasko, Giorgio Sacilotto, Dennis W. Dickson, Günter U. Höglinger, Silvana Tesei, John Hardy, Carlo Colosimo, Eliezer Masliah, Pia Winter, Joseph Jankovic, William W. Seeley, Claudio Mariani, David E. Riley, Matthew J. Farrer, Angelo Antonini, Jens Carsten Möller, Alex Rajput, Hans A. Kretzschmar, Nenad Bogdanovic, Nadine M. Melhem, Ulrich Müller, Steven E. Arnold, Wolfgang H. Oertel, Jorge L. Juncos, Rachel G. Gross, Daniela Berg, Rajesh Pahwa, Deborah A. Hall, Alexandra Durr, Chris Zarow, Lili-Naz Hazrati, Virginia M.-Y. Lee, Justo Garcãa De Yebenes, Donatella Ottaviani, John C. van Swieten, Tamas Revesz, John Q. Trojanowski, Zbigniew K. Wszolek, Sigrun Roeber, Werner Poewe, Matthias Höllerhage, Neill R. Graff-Radford, Laura B. Cantwell, Elena Alonso, Irene Litvan, Claire Troakes, Patrick M. A. Sleiman, Peter St George-Hyslop, Isabelle Leber, Lawrence I. Golbe, Chang En Yu, Allissa Dillman, Anna Zecchinelli, Stephen G. Reich, Stefano Goldwurm, Salvatore Spina, Eduardo Tolosa, Vivianna M. Van Deerlin, Charles L. White, Agnita J.W. Boon, Andrew B. Singleton, Huw R. Morris, Mi Ryung Han, Dena G. Hernandez, Carles Gaig, Matthew P. Frosch, Sebastiaan Engelborghs, Juan C. Troncoso, Roberto Cilia, Catriona McLean, Thomas Gasser, Robyn Flook, Barbara Borroni, Rohan de Silva, Murray Grossman, Martin N. Rossor, Bruce L. Miller, Sean S. O'Sullivan, Hakon Hakonarson, Walter Maetzler, Thomas D. Bird, David G. Standaert, Gesine Respondek, Marcel P. van der Brug, Sherry Beecher, Howard I. Hurtig, Gregor K. Wenning, J. Raphael Gibbs, Alexis Brice, Stuart Pickering-Brown, Jonathan D. Rohrer, Christopher Morris, Jana Vandrovcova, Giovanni Fabbrini, Jesús Avila, Owen A. Ross, Margherita Canesi, Lambertus Klei, Andrew P. Lieberman, Bernardino Ghetti, Laura Silveira-Moriyama, Peter Heutink, Pau Pastor, Nicoletta Meucci, Evan T. Geller, Luke A. Massey, Wang Zheng Chiu, Laura Donker Kaat, Maria Stamelou, Brit Mollenhauer, Mark R. Cookson, Thomas G. Beach, Novartis, Federal Ministry of Education and Research (Germany), Helmholtz Association, European Commission, Human genetics, NCA - Neurodegeneration, Neurology, Foundation for the National Institutes of Health, National Institute of Mental Health (US), German Genomics Initiative, German Research Foundation, Medical Research Council (UK), NIHR Biomedical Research Centre (UK), Harvard Brain Tissue Resource Center, Telethon Italia, Canadian Institutes of Health Research, Mayo Clinic, Nafarroako Gobernua, Fondazione Grigioni per il Morbo di Parkinson, De Deyn, Peter Paul, Engelborghs, Sebastiaan, and PSP Genetics Study Group
Subjects: pathology [Tauopathies], Genome-wide association study, Neurodegenerative, Medical and Health Sciences, Cohort Studies, 0302 clinical medicine, Degenerative disease, Risk Factors, Corticobasal degeneration, GWAS, 2.1 Biological and endogenous factors, Supranuclear Palsy, Chromosomes, Human, EIF2AK3, Aetiology, Genetics, Pediatric, 0303 health sciences, genetics [Supranuclear Palsy, Progressive], Single Nucleotide, Biological Sciences, Prognosis, 3. Good health, Frontotemporal Dementia (FTD), Tauopathies, Neurological, genetics [Polymorphism, Single Nucleotide], Tauopathy, Brain diseases, Supranuclear Palsy, Progressive, Palsy, Human, pathology [Supranuclear Palsy, Progressive], Single-nucleotide polymorphism, MAPT protein, human, tau Proteins, Neuropathology, Progressive Supranuclear Palsy, Biology, genetics [Chromosomes, Human], Polymorphism, Single Nucleotide, Chromosomes, Article, Progressive supranuclear palsy, PSP Genetics Study Group, 03 medical and health sciences, Rare Diseases, Progressive, ddc:570, medicine, Acquired Cognitive Impairment, Humans, Genetic Predisposition to Disease, Polymorphism, 030304 developmental biology, Cerebral Palsy, Prevention, Human Genome, genetics [Tauopathies], Neurosciences, Genetic Variation, Perinatal Period - Conditions Originating in Perinatal Period, medicine.disease, eye diseases, Brain Disorders, genetics [tau Proteins], Genetic Loci, Case-Control Studies, Dementia, Human medicine, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract: Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common being Alzheimer’s disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 PSP cases and 3,247 controls (Stage 1) followed up by a second stage where 1,051 cases and 3,560 controls were genotyped for Stage 1 SNPs that yielded P ≤ 10−3. We found significant novel signals (P < 5 × 10−8) associated with PSP risk at STX6, EIF2AK3, and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response, and for a myelin structural component., T.G. serves as an editorial board member of Movement Disorders and Parkinsonism and Related Disorders and is funded by Novartis Pharma, the Federal Ministry of Education and Research (BMBF) (NGFN-Plus and ERA-Net NEURON), the Helmholtz Association (HelMA, Helmholtz Alliance for Health in an Ageing Society) and the European Community (MeFoPa, Medndelian Forms of Parkinsonism). T.G. received speakers honoraria from Novartis, Merck-Serono, Schwarz Pharma, Boehringer Ingelheim and Valeant Pharma and royalties for his consulting activities from Cefalon Pharma and Merck-Serono. T.G. holds a patent concerning the LRRK2 gene and neurodegenerative disorders. J.H. is consulting for Merck Serono and Eisai. I.Litvan is the founder of the Litvan Neurological Research Foundation, whose mission is to increase awareness, determine the cause/s and search for a cure for neurodegenerative disorders presenting with either parkinsonian or dementia symptoms (501c3).
Published: 2011

39. Consanguinity associated with increased risk for bipolar I disorder in Egypt

Author: Bernie Devlin, Warda Fathi, Joel Wood, Farha A El-Chennawi, Hala El-Boraie, Salwa Tobar, Mohamed Shahda, Mohamed El-Sayed, Hanan Gaafar, Mai Elassy, Wafaa El-Bahaei, Nahed E. Ibrahim, Hala Salah, Ahmed Eissa, Eman El Sheshtawy, Hader Mansour, Vishwajit L. Nimgaonkar, Kodavali V. Chowdari, Osama El-Boraie, Amal Yassin, Lambertus Klei, and Michael E. Talkowski
Subjects: Adult, Male, medicine.medical_specialty, Bipolar Disorder, Bipolar I disorder, Population, Consanguinity, Polymerase Chain Reaction, Article, Interviews as Topic, Cellular and Molecular Neuroscience, Pregnancy, Risk Factors, Epidemiology, Humans, Medicine, Marriage, Family history, Risk factor, education, Genetics (clinical), Genetics, education.field_of_study, Cultural Characteristics, Polymorphism, Genetic, business.industry, Case-control study, medicine.disease, Psychiatry and Mental health, Case-Control Studies, Egypt, Female, business, Inbreeding, Microsatellite Repeats, Demography
Abstract: We aimed to contrast rates of consanguinity among patients with bipolar I disorder (BP1) and controls in a population with customary consanguineous marriages (i.e., marriage between related individuals). Consanguinity increases risk for numerous monogenic and polygenic diseases. Whether the risk for BP1 increases with consanguinity has not been investigated systematically. Two independent studies were conducted in Egypt: (1) Case–control study 93 patients with BP1, 90 screened adult control individuals, and available parents. The inbreeding coefficient/consanguinity rate was estimated in two ways: using 64 DNA polymorphisms (“DNA-based” rate); and from family history data (“self report”); (2) Epidemiological survey: total of 1,584 individuals were screened, from whom self-reported consanguinity data were obtained for identified BP1 cases (n=35) and 150 randomly selected, unaffected control individuals. DNA-based consanguinity rates showed significant case–control control differences (P=0.0039). Self-reported consanguinity rates were also elevated among BP1 patients in both samples (Study #1 OR=2.66, 95% confidence intervals, CI: 1.34, 5.29; Study #2: OR=4.64, 95% CI: 2.01, 10.34). In conclusion, two independent, systematic studies indicate increased consanguinity among Egyptian BP1 patients in the Nile delta region. Self-reported estimates of consanguinity are bolstered by DNA-based estimates, and both show significant case–control differences for BP1.
Published: 2009

40. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes

Author: Joseph Piven, Edward C. Frackelton, Christopher J. McDougle, Patrick M. A. Sleiman, Rosetta M. Chiavacci, John A. Sweeney, Guiqing Cai, Gerard D. Schellenberg, Camille W. Brune, Cuiping Hou, Shana M. Michaels, Rachel M. Game, Wendy Glaberson, Kai Wang, Raphael Bernier, Maja Bucan, Danielle Zurawiecki, Susan E. Levy, Alexander Kolevzon, Hilary Coon, Jeremy M. Silverman, Cecilia E. Kim, Latha Soorya, Nancy J. Minshew, Danielle S. Rudd, David J. Posey, Kacie J. Meyer, James H. Flory, Geraldine Dawson, Emily L. Crawford, Lea K. Davis, Judith Miller, Lambertus Klei, James S. Sutcliffe, Maria Garris, Evdokia Anagnostou, Annette Estes, Marcin Imielinski, Kelly A. Thomas, John I. Nurnberger, Struan F.A. Grant, Thomas H. Wassink, Hakon Hakonarson, Jonathan P. Bradfield, Edwin H. Cook, Bernie Devlin, Frederick G. Otieno, Joseph D. Buxbaum, Shawn Wood, Takeshi Sakurai, Robert T. Schultz, Jeffrey Munson, Thomas Owley, Kiran Annaiah, Joseph T. Glessner, Jennifer Reichert, Haitao Zhang, William M. McMahon, and Olena Korvatska
Subjects: Genotype, Cell Adhesion Molecules, Neuronal, Gene Dosage, Epigenetics of autism, Biology, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Article, Cohort Studies, mental disorders, Genetic variation, medicine, Pervasive developmental disorder, Humans, Gene Regulatory Networks, Genetic Predisposition to Disease, Heritability of autism, Copy-number variation, Autistic Disorder, Neurons, Genetics, Multidisciplinary, Genome, Human, Ubiquitin, Genetic Variation, Reproducibility of Results, medicine.disease, Human genetics, Europe, Developmental disorder, Case-Control Studies, Autism
Abstract: Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with approximately 550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 x 10(-3)). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 x 10(-3)). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 x 10(-6)). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.
Published: 2009

41. Genetic liability to schizophrenia in Oceanic Palau: a search in the affected and maternal generation

Author: Lambertus Klei, Marina Myles-Worsley, Kathryn Roeder, Josepha Tiobech, Caleb Otto, William Byerley, and Bernie Devlin
Subjects: Male, Psychosis, Linkage disequilibrium, Offspring, Palau, Population, Genes, Recessive, Biology, Models, Biological, Linkage Disequilibrium, Pregnancy, Genetics, medicine, Humans, Genetic Predisposition to Disease, Neural Tube Defects, Allele, education, Alleles, Genetics (clinical), education.field_of_study, Rh-Hr Blood-Group System, Models, Genetic, Brain, medicine.disease, Human genetics, Pregnancy Complications, Diabetes, Gestational, Schizophrenia, Blood Group Incompatibility, Microsatellite, Female, Microsatellite Repeats
Abstract: While liability to schizophrenia (Scz) is due to genetic and environmental factors, specific factors are largely unknown. We postulate a two-hit model for Scz, in which initial liability is generated during fetal brain development: this "hit" is precipitated by environmental stressors biologically interacting with maternal genetic vulnerability to the stress. Additional liability to Scz is generated by individual genetic vulnerability. To evaluate these putative levels of vulnerability, we search in the genome of both affected individuals and their mothers for variation that differs, statistically, from that in the general population. For parental analyses, mothers were treated as "affected," rather than their offspring, and the fathers were treated as "controls". We used a sample from the Palauan population: 175 individuals diagnosed with Scz, broadly defined; 87 mothers and 45 fathers of affected individuals. Pedigree and diagnostic data were available on 2,953 living and deceased subjects. DNA from 553 individuals was genotyped for short tandem repeats (STR) spaced approximately every 10 cM across the genome. We tested for association between affection status and STR alleles; such an approach was reasonable, despite the widely spaced markers, because this population has far-ranging linkage disequilibrium (LD). Results for the truly affected individuals were modest, whereas results from the maternal generation were promising. For a recessive model and a test for excess allele matching across mothers, significant findings occurred for D20S481, D10S1221, D6S1021, D13S317, and D18S976. Regions in which at least two adjacent markers produced substantial association statistics include 2p12-11.2, 2q24.1-32.1, 6q12-14.1, 10q23.2-24.21, 12q23.2-24.21 and 17q23.2-23.3.
Published: 2007

42. Testing for association based on excess allele sharing in a sample of related cases and controls

Author: Lambertus Klei and Kathyrn Roeder
Subjects: Genetic Markers, Male, Genetics, Linkage disequilibrium, Models, Statistical, Haplotype, Transmission disequilibrium test, Biology, Polymorphism, Single Nucleotide, Pedigree, Minor allele frequency, Gene Frequency, Genetic Techniques, Haplotypes, Humans, Female, Genetic Predisposition to Disease, Allele, Allele frequency, Genetics (clinical), Statistic, Genetic association
Abstract: Samples consisting of a mix of unrelated cases and controls, small pedigrees, and much larger pedigrees present a unique challenge for association studies. Few methods are available for efficient analysis of such a broad spectrum of data structures. In this paper we introduce a new matching statistic that is well suited to complex data structures and compare it with frequency-based methods available in the literature. To investigate and compare the power of these methods we simulate datasets based on complex pedigrees. We examine the influence of various levels of linkage disequilibrium (LD) of the disease allele with a marker allele (or equivalently a haplotype). For low frequency marker alleles/haplotypes, frequency-based statistics are more powerful in detecting association. In contrast, for high frequency marker alleles, the matching statistic has greater power. The highest power for frequency-based statistics occurs when the disease allele frequency closely matches the frequency of the linked marker allele. In contrast maximum power of the matching statistic always occurs for intermediate marker allele frequency regardless of the disease allele frequency. Moreover, the matching and frequency-based statistics exhibit little correlation. We conclude that these two approaches can be viewed as complementary in finding possible association between a disease and a marker for many different situations.
Published: 2007

43. A genome-wide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?

Author: James S. Sutcliffe, Timothy W. Yu, Dorothy E. Grice, Matthew W. State, Stephen Sanders, David H. Ledbetter, A. Jeremy Willsey, Vanessa Hus, Bernie Devlin, Christopher A. Walsh, Eric Fombonne, Daniel H. Geschwind, Michael T. Murtha, Christa Lese Martin, Lambertus Klei, Daniel Moreno-De-Luca, Jennifer K. Lowe, Shrikant Mane, Edwin H. Cook, Pauline Chaste, Catherine Lord, Eric M. Morrow, Donna M. Martin, and Arthur L. Beaudet
Subjects: Male, Autism Spectrum Disorder, Autism, Intellectual and Developmental Disabilities (IDD), Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Medical and Health Sciences, Article, Genetic variation, medicine, Genetics, Humans, GWAS, Heritability of autism, Genetic Predisposition to Disease, Family, Genetic Testing, Allele, Autistic Disorder, Polymorphism, Biological Psychiatry, Genetic association, Pediatric, Psychiatry, Genetic heterogeneity, Human Genome, Psychology and Cognitive Sciences, Genetic Variation, Single Nucleotide, Heritability, Biological Sciences, medicine.disease, Brain Disorders, Phenotype, Mental Health, Power, Female, Heterogeneity, Genome-Wide Association Study
Abstract: Background Phenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of subphenotyping of a well-characterized autism spectrum disorder (ASD) sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD. Methods Genome-wide genotypic data of 2576 families from the Simons Simplex Collection were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study, as well as estimating heritability and evaluating allele scores for each phenotypic subgroup. Results Association analyses revealed no genome-wide significant association signal. Subphenotyping did not increase power substantially. Moreover, allele scores built from the most associated single nucleotide polymorphisms, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups. Conclusions In genome-wide association analysis of the Simons Simplex Collection sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of subphenotypes is not a productive path forward for discovering genetic risk variants in ASD.
Published: 2015

44. The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment

Author: Wei Niu, Steven K. Reilly, Jun Yin, A. Jeremy Willsey, Jing Lei, Stephen Sanders, Mihovil Pletikos, Bernie Devlin, Li Liu, Candace Bichsel, Justin Cotney, Matthew W. State, Rebecca A. Muhle, Kathryn Roeder, Andrew T.N. Tebbenkamp, Wenzhong Liu, Nenad Sestan, James P. Noonan, and Lambertus Klei
Subjects: genetic structures, Autism Spectrum Disorder, Models, Neurological, Gene regulatory network, General Physics and Astronomy, Biology, Nervous System, behavioral disciplines and activities, Article, General Biochemistry, Genetics and Molecular Biology, Chromodomain, Mice, 03 medical and health sciences, 0302 clinical medicine, Neural Stem Cells, mental disorders, medicine, Animals, Humans, Gene Regulatory Networks, Loss function, 030304 developmental biology, Genetics, 0303 health sciences, Gene knockdown, Multidisciplinary, Gene Expression Regulation, Developmental, General Chemistry, Human brain, Chromatin Assembly and Disassembly, medicine.disease, Chromatin, DNA-Binding Proteins, medicine.anatomical_structure, Autism spectrum disorder, Gene Knockdown Techniques, Autism, 030217 neurology & neurosurgery, Transcription Factors
Abstract: Recent studies implicate chromatin modifiers in autism spectrum disorder (ASD) through the identification of recurrent de novo loss of function mutations in affected individuals. ASD risk genes are co-expressed in human midfetal cortex, suggesting that ASD risk genes converge in specific regulatory networks during neurodevelopment. To elucidate such networks, we identify genes targeted by CHD8, a chromodomain helicase strongly associated with ASD, in human midfetal brain, human neural stem cells (hNSCs) and embryonic mouse cortex. CHD8 targets are strongly enriched for other ASD risk genes in both human and mouse neurodevelopment, and converge in ASD-associated co-expression networks in human midfetal cortex. CHD8 knockdown in hNSCs results in dysregulation of ASD risk genes directly targeted by CHD8. Integration of CHD8-binding data into ASD risk models improves detection of risk genes. These results suggest loss of CHD8 contributes to ASD by perturbing an ancient gene regulatory network during human brain development., Autism genes converge in midfetal cortical co-expression networks, and chromatin regulators such as CHD8 are increasingly associated with autism spectrum disorder (ASD). Here the authors map CHD8 targets in developing brain, and find that CHD8 directly regulates other ASD risk genes during human neurodevelopment.
Published: 2015

45. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

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

46. Joint Analysis of Psychiatric Disorders Increases Accuracy of Risk Prediction for Schizophrenia, Bipolar Disorder, and Major Depressive Disorder

Author: Robert Maier, Gerhard Moser, Guo-Bo Chen, Stephan Ripke, William Coryell, James B. Potash, William A. Scheftner, Jianxin Shi, Myrna M. Weissman, Christina M. Hultman, Mikael Landén, Douglas F. Levinson, Kenneth S. Kendler, Jordan W. Smoller, Naomi R. Wray, S. Hong Lee, Devin Absher, Ingrid Agartz, Huda Akil, Farooq Amin, Ole A. Andreassen, Adebayo Anjorin, Richard Anney, Dan E. Arking, Philip Asherson, Maria H. Azevedo, Lena Backlund, Judith A. Badner, Anthony J. Bailey, Tobias Banaschewski, Jack D. Barchas, Michael R. Barnes, Thomas B. Barrett, Nicholas Bass, Agatino Battaglia, Michael Bauer, Mònica Bayés, Frank Bellivier, Sarah E. Bergen, Wade Berrettini, Catalina Betancur, Thomas Bettecken, Joseph Biederman, Elisabeth B. Binder, Donald W. Black, Douglas H.R. Blackwood, Cinnamon S. Bloss, Michael Boehnke, Dorret I. Boomsma, Gerome Breen, René Breuer, Richard Bruggeman, Nancy G. Buccola, Jan K. Buitelaar, William E. Bunney, Joseph D. Buxbaum, William F. Byerley, Sian Caesar, Wiepke Cahn, Rita M. Cantor, Miguel Casas, Aravinda Chakravarti, Kimberly Chambert, Khalid Choudhury, Sven Cichon, C. Robert Cloninger, David A. Collier, Edwin H. Cook, Hilary Coon, Bru Cormand, Paul Cormican, Aiden Corvin, William H. Coryell, Nicholas Craddock, David W. Craig, Ian W. Craig, Jennifer Crosbie, Michael L. Cuccaro, David Curtis, Darina Czamara, Mark J. Daly, Susmita Datta, Geraldine Dawson, Richard Day, Eco J. De Geus, Franziska Degenhardt, Bernie Devlin, Srdjan Djurovic, Gary J. Donohoe, Alysa E. Doyle, Jubao Duan, Frank Dudbridge, Eftichia Duketis, Richard P. Ebstein, Howard J. Edenberg, Josephine Elia, Sean Ennis, Bruno Etain, Ayman Fanous, Stephen V. Faraone, Anne E. Farmer, I. Nicol Ferrier, Matthew Flickinger, Eric Fombonne, Tatiana Foroud, Josef Frank, Barbara Franke, Christine Fraser, Robert Freedman, Nelson B. Freimer, Christine M. Freitag, Marion Friedl, Louise Frisén, Louise Gallagher, Pablo V. Gejman, Lyudmila Georgieva, Elliot S. Gershon, Daniel H. Geschwind, Ina Giegling, Michael Gill, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Tiffany A. Greenwood, Dorothy E. Grice, Magdalena Gross, Detelina Grozeva, Weihua Guan, Hugh Gurling, Lieuwe De Haan, Jonathan L. Haines, Hakon Hakonarson, Joachim Hallmayer, Steven P. Hamilton, Marian L. Hamshere, Thomas F. Hansen, Annette M. Hartmann, Martin Hautzinger, Andrew C. Heath, Anjali K. Henders, Stefan Herms, Ian B. Hickie, Maria Hipolito, Susanne Hoefels, Peter A. Holmans, Florian Holsboer, Witte J. Hoogendijk, Jouke-Jan Hottenga, Vanessa Hus, Andrés Ingason, Marcus Ising, Stéphane Jamain, Ian Jones, Lisa Jones, Anna K. Kähler, René S. Kahn, Radhika Kandaswamy, Matthew C. Keller, John R. Kelsoe, James L. Kennedy, Elaine Kenny, Lindsey Kent, Yunjung Kim, George K. Kirov, Sabine M. Klauck, Lambertus Klei, James A. Knowles, Martin A. Kohli, Daniel L. Koller, Bettina Konte, Ania Korszun, Lydia Krabbendam, Robert Krasucki, Jonna Kuntsi, Phoenix Kwan, Niklas Långström, Mark Lathrop, Jacob Lawrence, William B. Lawson, Marion Leboyer, David H. Ledbetter, Phil H. Lee, Todd Lencz, Klaus-Peter Lesch, Cathryn M. Lewis, Jun Li, Paul Lichtenstein, Jeffrey A. Lieberman, Dan-Yu Lin, Don H. Linszen, Chunyu Liu, Falk W. Lohoff, Sandra K. Loo, Catherine Lord, Jennifer K. Lowe, Susanne Lucae, Donald J. MacIntyre, Pamela A.F. Madden, Elena Maestrini, Patrik K.E. Magnusson, Pamela B. Mahon, Wolfgang Maier, Anil K. Malhotra, Shrikant M. Mane, Christa L. Martin, Nicholas G. Martin, Manuel Mattheisen, Keith Matthews, Morten Mattingsdal, Steven A. McCarroll, Kevin A. McGhee, James J. McGough, Patrick J. McGrath, Peter McGuffin, Melvin G. McInnis, Andrew McIntosh, Rebecca McKinney, Alan W. McLean, Francis J. McMahon, William M. McMahon, Andrew McQuillin, Helena Medeiros, Sarah E. Medland, Sandra Meier, Ingrid Melle, Fan Meng, Jobst Meyer, Christel M. Middeldorp, Lefkos Middleton, Vihra Milanova, Ana Miranda, Anthony P. Monaco, Grant W. Montgomery, Jennifer L. Moran, Daniel Moreno-De-Luca, Gunnar Morken, Derek W. Morris, Eric M. Morrow, Valentina Moskvina, Bryan J. Mowry, Pierandrea Muglia, Thomas W. Mühleisen, Bertram Müller-Myhsok, Michael Murtha, Richard M. Myers, Inez Myin-Germeys, Benjamin M. Neale, Stan F. Nelson, Caroline M. Nievergelt, Ivan Nikolov, Vishwajit Nimgaonkar, Willem A. Nolen, Markus M. Nöthen, John I. Nurnberger, Evaristus A. Nwulia, Dale R. Nyholt, Michael C. O’Donovan, Colm O’Dushlaine, Robert D. Oades, Ann Olincy, Guiomar Oliveira, Line Olsen, Roel A. Ophoff, Urban Osby, Michael J. Owen, Aarno Palotie, Jeremy R. Parr, Andrew D. Paterson, Carlos N. Pato, Michele T. Pato, Brenda W. Penninx, Michele L. Pergadia, Margaret A. Pericak-Vance, Roy H. Perlis, Benjamin S. Pickard, Jonathan Pimm, Joseph Piven, Danielle Posthuma, Fritz Poustka, Peter Propping, Shaun M. Purcell, Vinay Puri, Digby J. Quested, Emma M. Quinn, Josep Antoni Ramos-Quiroga, Henrik B. Rasmussen, Soumya Raychaudhuri, Karola Rehnström, Andreas Reif, Marta Ribasés, John P. Rice, Marcella Rietschel, Kathryn Roeder, Herbert Roeyers, Lizzy Rossin, Aribert Rothenberger, Guy Rouleau, Douglas Ruderfer, Dan Rujescu, Alan R. Sanders, Stephan J. Sanders, Susan L. Santangelo, Russell Schachar, Martin Schalling, Alan F. Schatzberg, Gerard D. Schellenberg, Stephen W. Scherer, Nicholas J. Schork, Thomas G. Schulze, Johannes Schumacher, Markus Schwarz, Edward Scolnick, Laura J. Scott, Joseph A. Sergeant, Paul D. Shilling, Stanley I. Shyn, Jeremy M. Silverman, Pamela Sklar, Susan L. Slager, Susan L. Smalley, Johannes H. Smit, Erin N. Smith, Edmund J.S. Sonuga-Barke, David St Clair, Matthew State, Michael Steffens, Hans-Christoph Steinhausen, John S. Strauss, Jana Strohmaier, T. Scott Stroup, Patrick F. Sullivan, James Sutcliffe, Peter Szatmari, Szabocls Szelinger, Anita Thapar, Srinivasa Thirumalai, Robert C. Thompson, Alexandre A. Todorov, Federica Tozzi, Jens Treutlein, Jung-Ying Tzeng, Manfred Uhr, Edwin J.C.G. van den Oord, Gerard Van Grootheest, Jim Van Os, Astrid M. Vicente, Veronica J. Vieland, John B. Vincent, Peter M. Visscher, Christopher A. Walsh, Thomas H. Wassink, Stanley J. Watson, Lauren A. Weiss, Thomas Werge, Thomas F. Wienker, Durk Wiersma, Ellen M. Wijsman, Gonneke Willemsen, Nigel Williams, A. Jeremy Willsey, Stephanie H. Witt, Wei Xu, Allan H. Young, Timothy W. Yu, Stanley Zammit, Peter P. Zandi, Peng Zhang, Frans G. Zitman, Sebastian Zöllner, University of Zurich, Lee, S Hong, Epidemiology and Data Science, Psychiatry, EMGO - Mental health, NCA - Neurobiology of mental health, Human genetics, NCA - Brain mechanisms in health and disease, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Maier, Robert, Moser, Gerhard, Chen, Guo-Bo, Ripke, Stephan, Coryell, William, Potash, James B, Scheftner, William A, Shi, Jianxin, Weissman, Myrna M, Hultman, Christina M, Landen, Mikael, Levinson, Douglas F, Kendler, Kenneth S, Smoller, Jordan, Wray, Naomi R, Cross-Disorder Working Group of the Psychiatric Genomics Consortium, Oades, Robert D. (Beitragende*r), Génétique de l'autisme = Genetics of Autism (NPS-01), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of St Andrews. School of Medicine, University of St Andrews. Institute of Behavioural and Neural Sciences, Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-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)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANS - Amsterdam Neuroscience, Adult Psychiatry, Child Psychiatry, Maier R., Moser G., Chen G.-B., Ripke S., Coryell W., Potash J.B., Scheftner W.A., Shi J., Weissman M.M., Hultman C.M., Landen M., Levinson D.F., Kendler K.S., Smoller J.W., Wray N.R., Lee S.H., Absher D., Agartz I., Akil H., Amin F., Andreassen O.A., Anjorin A., Anney R., Arking D.E., Asherson P., Azevedo M.H., Backlund L., Badner J.A., Bailey A.J., Banaschewski T., Barchas J.D., Barnes M.R., Barrett T.B., Bass N., Battaglia A., Bauer M., Bayes M., Bellivier F., Bergen S.E., Berrettini W., Betancur C., Bettecken T., Biederman J., Binder E.B., Black D.W., Blackwood D.H.R., Bloss C.S., Boehnke M., Boomsma D.I., Breen G., Breuer R., Bruggeman R., Buccola N.G., Buitelaar J.K., Bunney W.E., Buxbaum J.D., Byerley W.F., Caesar S., Cahn W., Cantor R.M., Casas M., Chakravarti A., Chambert K., Choudhury K., Cichon S., Robert Cloninger C., Collier D.A., Cook E.H., Coon H., Cormand B., Cormican P., Corvin A., Coryell W.H., Craddock N., Craig D.W., Craig I.W., Crosbie J., Cuccaro M.L., Curtis D., Czamara D., Daly M.J., Datta S., Dawson G., Day R., De Geus E.J., Degenhardt F., Devlin B., Djurovic S., Donohoe G.J., Doyle A.E., Duan J., Dudbridge F., Duketis E., Ebstein R.P., Edenberg H.J., Elia J., Ennis S., Etain B., Fanous A., Faraone S.V., Farmer A.E., Nicol Ferrier I., Flickinger M., Fombonne E., Foroud T., Frank J., Franke B., Fraser C., Freedman R., Freimer N.B., Freitag C.M., Friedl M., Frisen L., Gallagher L., Gejman P.V., Georgieva L., Gershon E.S., Geschwind D.H., Giegling I., Gill M., Gordon S.D., Gordon-Smith K., Green E.K., Greenwood T.A., Grice D.E., Gross M., Grozeva D., Guan W., Gurling H., De Haan L., Haines J.L., Hakonarson H., Hallmayer J., Hamilton S.P., Hamshere M.L., Hansen T.F., Hartmann A.M., Hautzinger M., Heath A.C., Henders A.K., Herms S., Hickie I.B., Hipolito M., Hoefels S., Holmans P.A., Holsboer F., Hoogendijk W.J., Hottenga J.-J., Hus V., Ingason A., Ising M., Jamain S., Jones I., Jones L., Kahler A.K., Kahn R.S., Kandaswamy R., Keller M.C., Kelsoe J.R., Kennedy J.L., Kenny E., Kent L., Kim Y., Kirov G.K., Klauck S.M., Klei L., Knowles J.A., Kohli M.A., Koller D.L., Konte B., Korszun A., Krabbendam L., Krasucki R., Kuntsi J., Kwan P., Langstrom N., Lathrop M., Lawrence J., Lawson W.B., Leboyer M., Ledbetter D.H., Lee P.H., Lencz T., Lesch K.-P., Lewis C.M., Li J., Lichtenstein P., Lieberman J.A., Lin D.-Y., Linszen D.H., Liu C., Lohoff F.W., Loo S.K., Lord C., Lowe J.K., Lucae S., MacIntyre D.J., Madden P.A.F., Maestrini E., Magnusson P.K.E., Mahon P.B., Maier W., Malhotra A.K., Mane S.M., Martin C.L., Martin N.G., Mattheisen M., Matthews K., Mattingsdal M., McCarroll S.A., McGhee K.A., McGough J.J., McGrath P.J., McGuffin P., McInnis M.G., McIntosh A., McKinney R., McLean A.W., McMahon F.J., McMahon W.M., McQuillin A., Medeiros H., Medland S.E., Meier S., Melle I., Meng F., Meyer J., Middeldorp C.M., Middleton L., Milanova V., Miranda A., Monaco A.P., Montgomery G.W., Moran J.L., Moreno-De-Luca D., Morken G., Morris D.W., Morrow E.M., Moskvina V., Mowry B.J., Muglia P., Muhleisen T.W., Muller-Myhsok B., Murtha M., Myers R.M., Myin-Germeys I., Neale B.M., Nelson S.F., Nievergelt C.M., Nikolov I., Nimgaonkar V., Nolen W.A., Nothen M.M., Nurnberger J.I., Nwulia E.A., Nyholt D.R., O'Donovan M.C., O'Dushlaine C., Oades R.D., Olincy A., Oliveira G., Olsen L., Ophoff R.A., Osby U., Owen M.J., Palotie A., Parr J.R., Paterson A.D., Pato C.N., Pato M.T., Penninx B.W., Pergadia M.L., Pericak-Vance M.A., Perlis R.H., Pickard B.S., Pimm J., Piven J., Posthuma D., Poustka F., Propping P., Purcell S.M., Puri V., Quested D.J., Quinn E.M., Ramos-Quiroga J.A., Rasmussen H.B., Raychaudhuri S., Rehnstrom K., Reif A., Ribases M., Rice J.P., Rietschel M., Roeder K., Roeyers H., Rossin L., Rothenberger A., Rouleau G., Ruderfer D., Rujescu D., Sanders A.R., Sanders S.J., Santangelo S.L., Schachar R., Schalling M., Schatzberg A.F., Schellenberg G.D., Scherer S.W., Schork N.J., Schulze T.G., Schumacher J., Schwarz M., Scolnick E., Scott L.J., Sergeant J.A., Shilling P.D., Shyn S.I., Silverman J.M., Sklar P., Slager S.L., Smalley S.L., Smit J.H., Smith E.N., Sonuga-Barke E.J.S., St Clair D., State M., Steffens M., Steinhausen H.-C., Strauss J.S., Strohmaier J., Scott Stroup T., Sullivan P.F., Sutcliffe J., Szatmari P., Szelinger S., Thapar A., Thirumalai S., Thompson R.C., Todorov A.A., Tozzi F., Treutlein J., Tzeng J.-Y., Uhr M., van den Oord E.J.C.G., Van Grootheest G., Van Os J., Vicente A.M., Vieland V.J., Vincent J.B., Visscher P.M., Walsh C.A., Wassink T.H., Watson S.J., Weiss L.A., Werge T., Wienker T.F., Wiersma D., Wijsman E.M., Willemsen G., Williams N., Jeremy Willsey A., Witt S.H., Xu W., Young A.H., Yu T.W., Zammit S., Zandi P.P., Zhang P., Zitman F.G., and Zollner S.
Subjects: Netherlands Twin Register (NTR), Multifactorial Inheritance, Multivariate analysis, Bipolar Disorder, genome annotation, Medizin, R Medicine (General), Medical and Health Sciences, Genome-wide association studies, 0302 clinical medicine, 2.5 Research design and methodologies (aetiology), GWAS, Genetics(clinical), Aetiology, Multivariate Analysi, Genetics (clinical), Genetics & Heredity, bipolar disorder, 0303 health sciences, education.field_of_study, Depression, Mental Disorders, Single Nucleotide, 3rd-DAS, Biological Sciences, 10058 Department of Child and Adolescent Psychiatry, Serious Mental Illness, Psychiatric Disorders, 3. Good health, Mental Health, Schizophrenia, Mental Disorder, Linear Model, Major depressive disorder, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Risk assessment, Human, medicine.medical_specialty, 2716 Genetics (clinical), Genetics, Medical, Population, SNP, 610 Medicine & health, QH426 Genetics, Best linear unbiased prediction, Polymorphism, Single Nucleotide, Risk Assessment, 03 medical and health sciences, 1311 Genetics, Medical, Report, medicine, Genetics, Humans, Bipolar disorder, Genetic Testing, Polymorphism, education, Psychiatry, QH426, 030304 developmental biology, Depressive Disorder, Depressive Disorder, Major, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Cross-Disorder Working Group of the Psychiatric Genomics Consortium, Prevention, Human Genome, Major, medicine.disease, genetic risk prediction, R1, Brain Disorders, schizophrenia, Sample size determination, Perturbações do Desenvolvimento Infantil e Saúde Mental, Multivariate Analysis, Linear Models, business, depressive disorders, 030217 neurology & neurosurgery
Abstract: Cross-Disorder Working Group of the Psychiatric Genomics Consortium - Vicente A.M. Acessível em: http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25640677/ Genetic risk prediction has several potential applications in medical research and clinical practice and could be used, for example, to stratify a heterogeneous population of patients by their predicted genetic risk. However, for polygenic traits, such as psychiatric disorders, the accuracy of risk prediction is low. Here we use a multivariate linear mixed model and apply multi-trait genomic best linear unbiased prediction for genetic risk prediction. This method exploits correlations between disorders and simultaneously evaluates individual risk for each disorder. We show that the multivariate approach significantly increases the prediction accuracy for schizophrenia, bipolar disorder, and major depressive disorder in the discovery as well as in independent validation datasets. By grouping SNPs based on genome annotation and fitting multiple random effects, we show that the prediction accuracy could be further improved. The gain in prediction accuracy of the multivariate approach is equivalent to an increase in sample size of 34% for schizophrenia, 68% for bipolar disorder, and 76% for major depressive disorders using single trait models. Because our approach can be readily applied to any number of GWAS datasets of correlated traits, it is a flexible and powerful tool to maximize prediction accuracy. With current sample size, risk predictors are not useful in a clinical setting but already are a valuable research tool, for example in experimental designs comparing cases with high and low polygenic risk
Published: 2015

47. Linkage analysis of a completely ascertained sample of familial schizophrenics and bipolars from Palau, Micronesia

Author: Brandi Galke, Weiting Xie, Caleb Otto, Bernie Devlin, William Byerley, Lambertus Klei, Kathyrn Roeder, Silviu-Alin Bacanu, Josepha Tiobech, and Marina Myles-Worsley
Subjects: Psychosis, Bipolar Disorder, Genetic Linkage, Palau, Population, Pedigree chart, Biology, Genetic linkage, Genetics, medicine, Humans, Bipolar disorder, education, Genetics (clinical), Linkage (software), education.field_of_study, medicine.disease, Human genetics, Pedigree, Schizophrenia, Chromosomes, Human, Pair 3, Lod Score, Chromosomes, Human, Pair 17, Microsatellite Repeats
Abstract: We report on linkage analysis of a completely ascertained population of familial psychosis derived from the oceanic nation of Palau. Palau, an archipelago of islands in the Southern Pacific, currently has a population of approximately 23,000 individuals. The peoples of Palau populated these islands recently in human history, approximately 2,000 years ago. As both historical and genetic evidence suggest, the population is far more homogeneous than most other populations undergoing genetic studies, and should therefore prove quite useful for mapping genetic variants having a meaningful impact on susceptibility to psychotic disorders. Moreover, for our study, essentially all on-island schizophrenics (150) and individuals with other psychotic disorders (25) participated. By analysis of narrow (only schizophrenia) and broad (all psychosis) diagnostic schemes, two-point linkage analyses suggest that two regions of the genome harbor genetic variants affecting liability in most families, 3q28 (LOD = 3.03) and 17q32.2 (LOD = 2.80). Results from individual pedigrees also support 2q37.2, 2p14, and 17p13 as potentially harboring important genetic variants. Most of these regions have been implicated in other genetic studies of psychosis in populations physically quite distant from this Oceanic population, although some (e.g., 3q28) appear to be novel results for schizophrenia linkage analyses.
Published: 2005

48. Combining Autism And Intellectual Disability Exome Data Implicates Disruption Of Neocortical Development In Both Disorders

Author: Kathryn Roeder, Ercument Cicek, Lambertus Klei, Bernie Devlin, Joseph D. Buxbaum, and Silvia De Rubeis
Subjects: Pharmacology, Genetics, 030506 rehabilitation, Neocortex, 05 social sciences, Biology, medicine.disease, Chromatin remodeling, 03 medical and health sciences, Psychiatry and Mental health, medicine.anatomical_structure, Neurology, Autism spectrum disorder, Intellectual disability, medicine, Autism, 0501 psychology and cognitive sciences, Pharmacology (medical), Neurology (clinical), 0305 other medical science, Prefrontal cortex, Exome, Gene, Biological Psychiatry, 050104 developmental & child psychology
Abstract: Background Autism spectrum disorder (ASD) and intellectual disability (ID) are known to be highly co-morbid, but whether their genetic risk converges on a common neurodevelopmental process is unknown. Integrative approaches using genetic evidence and brain co-expression data have proven useful in pinpointing specific developmental epochs and, within them, discrete neural circuits where risk for ASD maps. These analyses have shown that the strongest signal occurred in the neocortex, specifically in the prefrontal cortex and primary motor-somatosensory cortex (PFC), during mid-fetal development. However, it is unknown how ASD and ID risk intersect at this critical spatio-temporal window for neurodevelopment. These findings motivate a genetic analysis that contrasts and combines discoveries and leverage genetic evidence to shed light on the neurobiology underlying shared risk. Methods We used a statistical method called TADA (Transmission And De novo Association) to identify likely risk genes in ASD, ID and both disorders in 4,216 ASD and 1,479 ID families, as well as 869 ASD cases and 2,829 ancestry-matched controls. We integrated the genetic scores derived from the TADA analyses in ASD with the gene co-expression data from the BrainSpan mid-fetal PFC. The resulting DAWN network was evaluated to identify tightly integrated, functionally-related gene communities. We also conducted an analysis of single-cell RNA-sequencing data from single cells laser-microdissected from human neocortex specimens at 12 and 13 weeks post-conception (apical progenitors in the ventricular zone, subventricular basal progenitors, and neurons in the cortical plate). Results Using TADA, we defined genes associated with risk for ASD and ID (referred to as tASD, tID to denote TADA-implicated genes). Within the DAWN network built on the TADA scores in ASD and gene co-expression in the mid-fetal PFC, we identified two functionally related gene communities: the ‘chromatin modification’ and the ‘transcription factor’ community. Both communities were significantly enriched for tID genes, with the ‘chromatin modification’ community having the strongest enrichment. Notably, many of the transcription factors connected in the community belong to tightly regulated cascades that control the specification of laminar fate identity in progenitors and neurons. Protein-protein interaction analyses corroborated these conclusions, with two linked modules related to synaptic transmission, and another two related to chromatin modification. Within this critical spatio-temporal nexus for risk, apical (ap) and basal progenitors (bp), and neurons (n) are all strongly expressing for tASD genes, with a steady increase in the enrichment from types ap to bp to n. A milder and more symmetrically distributed enrichment was observed for tID genes. Discussion Our analyses of gene expression of mid-fetal neocortical cells and tissue-level co-expression implicate developmental disruption of cortical projection neurons in the etiology of both ASD and ID. Our analyses suggest that mutations in ASD risk genes prominently affect processes relevant to postmitotic neurons, while ID risk might extend to processes preceding acquisition of neuronal differentiation. Within these developmental frames, chromatin remodeling and transcriptional networks were reaffirmed as prominent pathways in both ASD and ID.
Published: 2017

49. DAWN: a framework to identify autism genes and subnetworks using gene expression and genetics

Author: Bernie Devlin, Stephen Sanders, Mingfeng Li, Abdullah Ercument Cicek, Lambertus Klei, Li Liu, Xin He, Rebecca A. Muhle, Nenad Sestan, Kathryn McFadden, Cong Lu, Jing Lei, Kathryn Roeder, Avi Ma'ayan, Arthur Jeremy Willsey, Yan Kou, James P. Noonan, Joseph D. Buxbaum, and Matthew W. State
Subjects: Proband, Gene discovery, Autism, Period (gene), Network, Biology, Neuronal arborization, Developmental Neuroscience, Weighted gene co-expression network analysis, mental disorders, Gene expression, medicine, Molecular Biology, Gene, Exome sequencing, Genetics, Research, medicine.disease, Risk prediction, Human genetics, Psychiatry and Mental health, Autism spectrum disorder, Neurite extension, Hidden Markov random field, Developmental Biology
Abstract: Background De novo loss-of-function (dnLoF) mutations are found twofold more often in autism spectrum disorder (ASD) probands than their unaffected siblings. Multiple independent dnLoF mutations in the same gene implicate the gene in risk and hence provide a systematic, albeit arduous, path forward for ASD genetics. It is likely that using additional non-genetic data will enhance the ability to identify ASD genes. Methods To accelerate the search for ASD genes, we developed a novel algorithm, DAWN, to model two kinds of data: rare variations from exome sequencing and gene co-expression in the mid-fetal prefrontal and motor-somatosensory neocortex, a critical nexus for risk. The algorithm casts the ensemble data as a hidden Markov random field in which the graph structure is determined by gene co-expression and it combines these interrelationships with node-specific observations, namely gene identity, expression, genetic data and the estimated effect on risk. Results Using currently available genetic data and a specific developmental time period for gene co-expression, DAWN identified 127 genes that plausibly affect risk, and a set of likely ASD subnetworks. Validation experiments making use of published targeted resequencing results demonstrate its efficacy in reliably predicting ASD genes. DAWN also successfully predicts known ASD genes, not included in the genetic data used to create the model. Conclusions Validation studies demonstrate that DAWN is effective in predicting ASD genes and subnetworks by leveraging genetic and gene expression data. The findings reported here implicate neurite extension and neuronal arborization as risks for ASD. Using DAWN on emerging ASD sequence data and gene expression data from other brain regions and tissues would likely identify novel ASD genes. DAWN can also be used for other complex disorders to identify genes and subnetworks in those disorders.
Published: 2014

50. Characterizing runs of homozygosity and their impact on risk for psychosis in a population isolate

Author: Frank A. Middleton, Shawn Wood, Kathryn Roeder, Cara Dresbold, Lambertus Klei, Nadine M. Melhem, Victor Yano, William Byerley, Cong Lu, Stephen V. Faraone, Marina Myles-Worsley, Sophia Vinogradov, Josepha Tiobech, and Bernie Devlin
Subjects: Psychosis, Palau, Clinical Sciences, Population, Locus (genetics), Runs of Homozygosity, Biology, Polymorphism, Single Nucleotide, Article, Cellular and Molecular Neuroscience, Clinical Research, Risk Factors, Genetics, medicine, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, psychosis, Polymorphism, Aetiology, education, Genetics (clinical), Alleles, education.field_of_study, Genome, Genome, Human, ROH, Homozygote, Neurosciences, Single Nucleotide, medicine.disease, Brain Disorders, schizophrenia, Psychiatry and Mental health, Mental Health, Haplotypes, Psychotic Disorders, Case-Control Studies, homozygosity, Human, Demography
Abstract: An increased abundance of runs of homozygosity (ROH) has been associated with risk for various diseases, including schizophrenia. Here we investigate the characteristics of ROH in Palau, an Oceanic population, evaluating whether these characteristics are related to risk for psychotic disorders and the nature of this association. To accomplish these aims we evaluate a sample of 203 cases with schizophrenia and related psychotic disorders-representing almost complete ascertainment of affected individuals in the population-and contrast their ROH to that of 125 subjects chosen to function as controls. While Palauan diagnosed with psychotic disorders tend to have slightly more ROH regions than controls, the distinguishing features are that they have longer ROH regions, greater total length of ROH, and their ROH tends to co-occur more often at the same locus. The nature of the sample allows us to investigate whether rare, highly penetrant recessive variants generate such case-control differences in ROH. Neither rare, highly penetrant recessive variants nor individual common variants of large effect account for a substantial proportion of risk for psychosis in Palau. These results suggest a more nuanced model for risk is required to explain patterns of ROH for this population.
Published: 2014

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