Search

Your search keyword '"Robinson, Elise B"' showing total 261 results
Start Over Author "Robinson, Elise B"
261 results on '"Robinson, Elise B"'

2. Principled distillation of UK Biobank phenotype data reveals underlying structure in human variation

Author

Carey, Caitlin E., Shafee, Rebecca, Wedow, Robbee, Elliott, Amanda, Palmer, Duncan S., Compitello, John, Kanai, Masahiro, Abbott, Liam, Schultz, Patrick, Karczewski, Konrad J., Bryant, Samuel C., Cusick, Caroline M., Churchhouse, Claire, Howrigan, Daniel P., King, Daniel, Davey Smith, George, Neale, Benjamin M., Walters, Raymond K., and Robinson, Elise B.

Published
2024
Full Text
View/download PDF

4. A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex

Author

Antaki, Danny, Guevara, James, Maihofer, Adam X, Klein, Marieke, Gujral, Madhusudan, Grove, Jakob, Carey, Caitlin E, Hong, Oanh, Arranz, Maria J, Hervas, Amaia, Corsello, Christina, Vaux, Keith K, Muotri, Alysson R, Iakoucheva, Lilia M, Courchesne, Eric, Pierce, Karen, Gleeson, Joseph G, Robinson, Elise B, Nievergelt, Caroline M, and Sebat, Jonathan

Subjects
Genetic Testing, Prevention, Intellectual and Developmental Disabilities (IDD), Brain Disorders, Mental Health, Genetics, Autism, Neurosciences, Pediatric, 2.1 Biological and endogenous factors, Aetiology, Autism Spectrum Disorder, Autistic Disorder, Child, Family, Female, Genetic Predisposition to Disease, Humans, Male, Multifactorial Inheritance, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

The genetic etiology of autism spectrum disorder (ASD) is multifactorial, but how combinations of genetic factors determine risk is unclear. In a large family sample, we show that genetic loads of rare and polygenic risk are inversely correlated in cases and greater in females than in males, consistent with a liability threshold that differs by sex. De novo mutations (DNMs), rare inherited variants and polygenic scores were associated with various dimensions of symptom severity in children and parents. Parental age effects on risk for ASD in offspring were attributable to a combination of genetic mechanisms, including DNMs that accumulate in the paternal germline and inherited risk that influences behavior in parents. Genes implicated by rare variants were enriched in excitatory and inhibitory neurons compared with genes implicated by common variants. Our results suggest that a phenotypic spectrum of ASD is attributable to a spectrum of genetic factors that impact different neurodevelopmental processes.

Published
2022

7. Statistical and functional convergence of common and rare genetic influences on autism at chromosome 16p

Author

Weiner, Daniel J., Ling, Emi, Erdin, Serkan, Tai, Derek J. C., Yadav, Rachita, Grove, Jakob, Fu, Jack M., Nadig, Ajay, Carey, Caitlin E., Baya, Nikolas, Bybjerg-Grauholm, Jonas, Berretta, Sabina, Macosko, Evan Z., Sebat, Jonathan, O’Connor, Luke J., Hougaard, David M., Børglum, Anders D., Talkowski, Michael E., McCarroll, Steven A., and Robinson, Elise B.

Published
2022
Full Text
View/download PDF

8. Identification of shared and differentiating genetic architecture for autism spectrum disorder, attention-deficit hyperactivity disorder and case subgroups

Author

Mattheisen, Manuel, Grove, Jakob, Als, Thomas D., Martin, Joanna, Voloudakis, Georgios, Meier, Sandra, Demontis, Ditte, Bendl, Jaroslav, Walters, Raymond, Carey, Caitlin E., Rosengren, Anders, Strom, Nora I., Hauberg, Mads Engel, Zeng, Biao, Hoffman, Gabriel, Zhang, Wen, Bybjerg-Grauholm, Jonas, Bækvad-Hansen, Marie, Agerbo, Esben, Cormand, Bru, Nordentoft, Merete, Werge, Thomas, Mors, Ole, Hougaard, David M., Buxbaum, Joseph D., Faraone, Stephen V., Franke, Barbara, Dalsgaard, Søren, Mortensen, Preben B., Robinson, Elise B., Roussos, Panos, Neale, Benjamin M., Daly, Mark J., and Børglum, Anders D.

Published
2022
Full Text
View/download PDF

9. Genetic correlates of phenotypic heterogeneity in autism

Author

Warrier, Varun, Zhang, Xinhe, Reed, Patrick, Havdahl, Alexandra, Moore, Tyler M., Cliquet, Freddy, Leblond, Claire S., Rolland, Thomas, Rosengren, Anders, Rowitch, David H., Hurles, Matthew E., Geschwind, Daniel H., Børglum, Anders D., Robinson, Elise B., Grove, Jakob, Martin, Hilary C., Bourgeron, Thomas, and Baron-Cohen, Simon

Published
2022
Full Text
View/download PDF

11. Identification of common genetic risk variants for autism spectrum disorder

Author

Grove, Jakob, Ripke, Stephan, Als, Thomas D, Mattheisen, Manuel, Walters, Raymond K, Won, Hyejung, Pallesen, Jonatan, Agerbo, Esben, Andreassen, Ole A, Anney, Richard, Awashti, Swapnil, Belliveau, Rich, Bettella, Francesco, Buxbaum, Joseph D, Bybjerg-Grauholm, Jonas, Bækvad-Hansen, Marie, Cerrato, Felecia, Chambert, Kimberly, Christensen, Jane H, Churchhouse, Claire, Dellenvall, Karin, Demontis, Ditte, De Rubeis, Silvia, Devlin, Bernie, Djurovic, Srdjan, Dumont, Ashley L, Goldstein, Jacqueline I, Hansen, Christine S, Hauberg, Mads Engel, Hollegaard, Mads V, Hope, Sigrun, Howrigan, Daniel P, Huang, Hailiang, Hultman, Christina M, Klei, Lambertus, Maller, Julian, Martin, Joanna, Martin, Alicia R, Moran, Jennifer L, Nyegaard, Mette, Nærland, Terje, Palmer, Duncan S, Palotie, Aarno, Pedersen, Carsten Bøcker, Pedersen, Marianne Giørtz, dPoterba, Timothy, Poulsen, Jesper Buchhave, Pourcain, Beate St, Qvist, Per, Rehnström, Karola, Reichenberg, Abraham, Reichert, Jennifer, Robinson, Elise B, Roeder, Kathryn, Roussos, Panos, Saemundsen, Evald, Sandin, Sven, Satterstrom, F Kyle, Davey Smith, George, Stefansson, Hreinn, Steinberg, Stacy, Stevens, Christine R, Sullivan, Patrick F, Turley, Patrick, Walters, G Bragi, Xu, Xinyi, Stefansson, Kari, Geschwind, Daniel H, Nordentoft, Merete, Hougaard, David M, Werge, Thomas, Mors, Ole, Mortensen, Preben Bo, Neale, Benjamin M, Daly, Mark J, and Børglum, Anders D

Subjects
Intellectual and Developmental Disabilities (IDD), Human Genome, Pediatric, Brain Disorders, Autism, Biotechnology, Genetics, Mental Health, Prevention, 2.3 Psychological, social and economic factors, Aetiology, 2.1 Biological and endogenous factors, Mental health, Adolescent, Autism Spectrum Disorder, Case-Control Studies, Child, Child, Preschool, Denmark, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium, BUPGEN, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, 23andMe Research Team, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.

Published
2019

12. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.

Author

Demontis, Ditte, Walters, Raymond K, Martin, Joanna, Mattheisen, Manuel, Als, Thomas D, Agerbo, Esben, Baldursson, Gísli, Belliveau, Rich, Bybjerg-Grauholm, Jonas, Bækvad-Hansen, Marie, Cerrato, Felecia, Chambert, Kimberly, Churchhouse, Claire, Dumont, Ashley, Eriksson, Nicholas, Gandal, Michael, Goldstein, Jacqueline I, Grasby, Katrina L, Grove, Jakob, Gudmundsson, Olafur O, Hansen, Christine S, Hauberg, Mads Engel, Hollegaard, Mads V, Howrigan, Daniel P, Huang, Hailiang, Maller, Julian B, Martin, Alicia R, Martin, Nicholas G, Moran, Jennifer, Pallesen, Jonatan, Palmer, Duncan S, Pedersen, Carsten Bøcker, Pedersen, Marianne Giørtz, Poterba, Timothy, Poulsen, Jesper Buchhave, Ripke, Stephan, Robinson, Elise B, Satterstrom, F Kyle, Stefansson, Hreinn, Stevens, Christine, Turley, Patrick, Walters, G Bragi, Won, Hyejung, Wright, Margaret J, ADHD Working Group of the Psychiatric Genomics Consortium (PGC), Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium, 23andMe Research Team, Andreassen, Ole A, Asherson, Philip, Burton, Christie L, Boomsma, Dorret I, Cormand, Bru, Dalsgaard, Søren, Franke, Barbara, Gelernter, Joel, Geschwind, Daniel, Hakonarson, Hakon, Haavik, Jan, Kranzler, Henry R, Kuntsi, Jonna, Langley, Kate, Lesch, Klaus-Peter, Middeldorp, Christel, Reif, Andreas, Rohde, Luis Augusto, Roussos, Panos, Schachar, Russell, Sklar, Pamela, Sonuga-Barke, Edmund JS, Sullivan, Patrick F, Thapar, Anita, Tung, Joyce Y, Waldman, Irwin D, Medland, Sarah E, Stefansson, Kari, Nordentoft, Merete, Hougaard, David M, Werge, Thomas, Mors, Ole, Mortensen, Preben Bo, Daly, Mark J, Faraone, Stephen V, Børglum, Anders D, and Neale, Benjamin M

Subjects
ADHD Working Group of the Psychiatric Genomics Consortium, Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium, 23andMe Research Team, Brain, Humans, Genetic Predisposition to Disease, Risk, Cohort Studies, Attention Deficit Disorder with Hyperactivity, Gene Expression Regulation, Polymorphism, Single Nucleotide, Adolescent, Child, Child, Preschool, Female, Male, Genome-Wide Association Study, Genetic Loci, Clinical Research, Mental Health, Human Genome, Pediatric, Prevention, Genetics, Brain Disorders, Attention Deficit Hyperactivity Disorder (ADHD), Behavioral and Social Science, Aetiology, 2.1 Biological and endogenous factors, Mental health, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

Published
2019

13. The female protective effect against autism spectrum disorder

Author

Wigdor, Emilie M., Weiner, Daniel J., Grove, Jakob, Fu, Jack M., Thompson, Wesley K., Carey, Caitlin E., Baya, Nikolas, van der Merwe, Celia, Walters, Raymond K., Satterstrom, F. Kyle, Palmer, Duncan S., Rosengren, Anders, Bybjerg-Grauholm, Jonas, Hougaard, David M., Mortensen, Preben Bo, Daly, Mark J., Talkowski, Michael E., Sanders, Stephan J., Bishop, Somer L., Børglum, Anders D., and Robinson, Elise B.

Published
2022
Full Text
View/download PDF

14. Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap

Author

Gandal, Michael J, Haney, Jillian R, Parikshak, Neelroop N, Leppa, Virpi, Ramaswami, Gokul, Hartl, Chris, Schork, Andrew J, Appadurai, Vivek, Buil, Alfonso, Werge, Thomas M, Liu, Chunyu, White, Kevin P, Horvath, Steve, Geschwind, Daniel H, Sestan, Nenad, Vaccarino, Flora, Gerstein, Mark, Weissman, Sherman, Pochareddy, Sirisha, State, Matthew, Knowles, James, Farnham, Peggy, Akbarian, Schahram, Pinto, Dalila, Van Baekl, Harm, Dracheva, Stella, Jaffe, Andrew, Hyde, Thomas, Zandi, Peter, Crawford, Gregory, Sullivan, Pat, Thompson, Wesley Kurt, Mortensen, Preben Bo, Agerbo, Esben, Pedersen, Marianne Giørtz, Pedersen, Carsten Bøcker, Mors, Ole, Børglum, Anders D, Nordentoft, Merete, Hougaard, David M, Bybjerg-Grauholm, Jonas, Bækvad-Hansen, Marie, Martin, Alicia R, Dumont, Ashley, Stevens, Christine, Churchhouse, Claire, Howrigan, Daniel P, Palmer, Duncan S, Robinson, Elise B, Satterstrom, Kyle F, Cerrato, Felecia, Huang, Hailiang, Goldstein, Jacqueline, Moran, Jennifer, Julian, Joanna Martin, Kimberly, Maller, Patrick, Chambert, Turley, Patrick, Walters, Raymond, Belliveau, Rich, Ripke, Stephan, Poterba, Timothy, Daly, Mark J, Neale, Benjamin, Fromer, Menachem, Roussos, Panos, Johnson, Jessica S, Shah, Hardik R, Mahajan, Milind C, Schadt, Eric, Haroutunian, Vahram, Ruderfer, Douglas M, Buxbaum, Joseph D, Sieberts, Solveig K, Dang, Kristen, Logsdon, Ben, Mangravite, Lara M, Peters, Mette, Gur, Raquel E, Hahn, Chang-Gyu, Devlin, Bernie, Klei, Lambertus L, Lewis, David, Lipska, Barbara, Hirai, Keisuke, Toyoshiba, Hiroyoshi, and Domenici, Enrico

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Biological Psychology, Psychology, Pharmacology and Pharmaceutical Sciences, Serious Mental Illness, Brain Disorders, Human Genome, Mental Health, Schizophrenia, Neurosciences, Bipolar Disorder, Depression, Mental Illness, 2.1 Biological and endogenous factors, Aetiology, Mental health, Good Health and Well Being, Cerebral Cortex, Gene Expression Profiling, Gene Expression Regulation, Genetic Predisposition to Disease, Humans, Mental Disorders, Multifactorial Inheritance, Nervous System Diseases, Polymorphism, Single Nucleotide, Transcription, Genetic, CommonMind Consortium, PsychENCODE Consortium, iPSYCH-BROAD Working Group, General Science & Technology
Abstract

The predisposition to neuropsychiatric disease involves a complex, polygenic, and pleiotropic genetic architecture. However, little is known about how genetic variants impart brain dysfunction or pathology. We used transcriptomic profiling as a quantitative readout of molecular brain-based phenotypes across five major psychiatric disorders-autism, schizophrenia, bipolar disorder, depression, and alcoholism-compared with matched controls. We identified patterns of shared and distinct gene-expression perturbations across these conditions. The degree of sharing of transcriptional dysregulation is related to polygenic (single-nucleotide polymorphism-based) overlap across disorders, suggesting a substantial causal genetic component. This comprehensive systems-level view of the neurobiological architecture of major neuropsychiatric illness demonstrates pathways of molecular convergence and specificity.

Published
2018

15. Genome-wide association meta-analysis of age at onset of walking

Author

Gui, Anna, primary, Hollowell, Anja, additional, Wigdor, Emilie M., additional, Morgan, Morgan J., additional, Hannigan, Laurie J., additional, Corfield, Elizabeth C., additional, Odintsova, Veronika, additional, Hottenga, Jouke-Jan, additional, Wong, Andrew, additional, Pool, René, additional, Cullen, Harriet, additional, Wilson, Siân, additional, Warrier, Varun, additional, Eilertsen, Espen M., additional, Andreassen, Ole A., additional, Middeldorp, Christel M., additional, Pourcain, Beate St, additional, Bartels, Meike, additional, Boomsma, Dorret I., additional, Hartman, Catharina A., additional, Robinson, Elise B., additional, Arichi, Tomoki, additional, Edwards, David, additional, Johnson, Mark H., additional, Dudbridge, Frank, additional, Sanders, Stephan J., additional, Havdahl, Alexandra, additional, and Ronald, Angelica, additional

Published
2024
Full Text
View/download PDF

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

Author

Weiner, Daniel J, Wigdor, Emilie M, Ripke, Stephan, Walters, Raymond K, Kosmicki, Jack A, Grove, Jakob, Samocha, Kaitlin E, Goldstein, Jacqueline I, Okbay, Aysu, Bybjerg-Grauholm, Jonas, Werge, Thomas, Hougaard, David M, Taylor, Jacob, Skuse, David, Devlin, Bernie, Anney, Richard, Sanders, Stephan J, Bishop, Somer, Mortensen, Preben Bo, Børglum, Anders D, Smith, George Davey, Daly, Mark J, and Robinson, Elise B

Subjects
Biological Sciences, Genetics, Autism, Brain Disorders, Prevention, Mental Health, Pediatric, Intellectual and Developmental Disabilities (IDD), 2.4 Surveillance and distribution, Aetiology, 2.1 Biological and endogenous factors, Mental health, Good Health and Well Being, Adult, Autism Spectrum Disorder, Child, Cohort Studies, Educational Status, Ethnicity, Family Health, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Genetics, Behavioral, Humans, Intellectual Disability, Intelligence, Male, Multifactorial Inheritance, Phenotype, Risk Factors, Schizophrenia, Sequence Deletion, iPSYCH-Broad Autism Group, Psychiatric Genomics Consortium Autism Group, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

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

Published
2017

17. Identification of Developmental and Behavioral Markers Associated With Genetic Abnormalities in Autism Spectrum Disorder

Author

Bishop, Somer L, Farmer, Cristan, Bal, Vanessa, Robinson, Elise B, Willsey, A Jeremy, Werling, Donna M, Havdahl, Karoline Alexandra, Sanders, Stephan J, and Thurm, Audrey

Subjects
Biological Psychology, Psychology, Genetic Testing, Clinical Research, Mental Health, Behavioral and Social Science, Brain Disorders, Autism, Pediatric Research Initiative, Intellectual and Developmental Disabilities (IDD), Genetics, Basic Behavioral and Social Science, Pediatric, 2.3 Psychological, social and economic factors, Aetiology, 2.1 Biological and endogenous factors, Mental health, Adolescent, Autism Spectrum Disorder, Case-Control Studies, Child, Child, Preschool, DNA Copy Number Variations, DNA Mutational Analysis, Developmental Disabilities, Female, Genotype, Humans, Intelligence, Language Development Disorders, Likelihood Functions, Male, Phenotype, Prognosis, Reference Values, De Novo Mutations, Idiopathic ASD, Simons Simplex Collection, Syndromic ASD, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Clinical and health psychology
Abstract

ObjectiveAside from features associated with risk of neurogenetic syndromes in general (e.g., cognitive impairment), limited progress has been made in identifying phenotype-genotype relationships in autism spectrum disorder (ASD). The objective of this study was to extend work in the Simons Simplex Collection by comparing the phenotypic profiles of ASD probands with or without identified de novo loss of function mutations or copy number variants in high-confidence ASD-associated genes or loci.MethodAnalyses preemptively accounted for documented differences in sex and IQ in affected individuals with de novo mutations by matching probands with and without these genetic events on sex, IQ, and age before comparing them on multiple behavioral domains.ResultsChildren with de novo mutations (N=112) had a greater likelihood of motor delay during early development (later age at walking), but they were less impaired on certain measures of ASD core symptoms (parent-rated social communication abnormalities and clinician-rated diagnostic certainty about ASD) in later childhood. These children also showed relative strengths in verbal and language abilities, including a smaller discrepancy between nonverbal and verbal IQ and a greater likelihood of having achieved fluent language (i.e., regular use of complex sentences).ConclusionsChildren with ASD with de novo mutations may exhibit a "muted" symptom profile with respect to social communication and language deficits relative to those with ASD with no identified genetic abnormalities. Such findings suggest that examining early milestone differences and standardized testing results may be helpful in etiologic efforts, and potentially in clinical differentiation of various subtypes of ASD, but only if developmental and demographic variables are properly accounted for first.

Published
2017

18. Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples

Author

Kosmicki, Jack A, Samocha, Kaitlin E, Howrigan, Daniel P, Sanders, Stephan J, Slowikowski, Kamil, Lek, Monkol, Karczewski, Konrad J, Cutler, David J, Devlin, Bernie, Roeder, Kathryn, Buxbaum, Joseph D, Neale, Benjamin M, MacArthur, Daniel G, Wall, Dennis P, Robinson, Elise B, and Daly, Mark J

Subjects
Biological Sciences, Genetics, Brain Disorders, Neurosciences, Biotechnology, Intellectual and Developmental Disabilities (IDD), Aetiology, 2.1 Biological and endogenous factors, Autism Spectrum Disorder, Exome, Genetic Predisposition to Disease, Genetic Variation, Humans, Intellectual Disability, Neurodevelopmental Disorders, Phenotype, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Recent research has uncovered an important role for de novo variation in neurodevelopmental disorders. Using aggregated data from 9,246 families with autism spectrum disorder, intellectual disability, or developmental delay, we found that ∼1/3 of de novo variants are independently present as standing variation in the Exome Aggregation Consortium's cohort of 60,706 adults, and these de novo variants do not contribute to neurodevelopmental risk. We further used a loss-of-function (LoF)-intolerance metric, pLI, to identify a subset of LoF-intolerant genes containing the observed signal of associated de novo protein-truncating variants (PTVs) in neurodevelopmental disorders. LoF-intolerant genes also carry a modest excess of inherited PTVs, although the strongest de novo-affected genes contribute little to this excess, thus suggesting that the excess of inherited risk resides in lower-penetrant genes. These findings illustrate the importance of population-based reference cohorts for the interpretation of candidate pathogenic variants, even for analyses of complex diseases and de novo variation.

Published
2017

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

Author

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

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

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

Published
2015

22. Publisher Correction: A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex

Author

Antaki, Danny, Guevara, James, Maihofer, Adam X., Klein, Marieke, Gujral, Madhusudan, Grove, Jakob, Carey, Caitlin E., Hong, Oanh, Arranz, Maria J., Hervas, Amaia, Corsello, Christina, Vaux, Keith K., Muotri, Alysson R., Iakoucheva, Lilia M., Courchesne, Eric, Pierce, Karen, Gleeson, Joseph G., Robinson, Elise B., Nievergelt, Caroline M., and Sebat, Jonathan

Published
2022
Full Text
View/download PDF

23. Paternal-Age-Related de Novo Mutations and Risk for Five Disorders

Author

Taylor, Jacob L., Debost, Jean-Christophe P. G., Morton, Sarah U., Wigdor, Emilie M., Heyne, Henrike O., Lal, Dennis, Howrigan, Daniel P., Bloemendal, Alex, Larsen, Janne T., Kosmicki, Jack A., Weiner, Daniel J., Homsy, Jason, Seidman, Jonathan G., Seidman, Christine E., Agerbo, Esben, McGrath, John J., Mortensen, Preben Bo, Petersen, Liselotte, Daly, Mark J., and Robinson, Elise B.

Published
2020
Full Text
View/download PDF

24. Phenotype and genetic analysis of data collected within the first year of NeuroDev

Author

Kipkemoi, Patricia, Kim, Heesu Ally, Christ, Bjorn, O’Heir, Emily, Allen, Jake, Austin-Tse, Christina, Baxter, Samantha, Brand, Harrison, Bryant, Sam, Buser, Nick, de Menil, Victoria, Eastman, Emma, Murugasen, Serini, Galvin, Alice, Kombe, Martha, Ngombo, Alfred, Mkubwa, Beatrice, Mwangi, Paul, Kipkoech, Collins, Lovgren, Alysia, MacArthur, Daniel G., Melly, Brigitte, Mwangasha, Katini, Martin, Alicia, Nkambule, Lethukuthula L., Sanchis-Juan, Alba, Singer-Berk, Moriel, Talkowski, Michael E., VanNoy, Grace, van der Merwe, Celia, Newton, Charles, O’Donnell-Luria, Anne, Abubakar, Amina, Donald, Kirsten A., and Robinson, Elise B.

Published
2023
Full Text
View/download PDF

25. Paternal-age-related de novo mutations and risk for five disorders

Author

Taylor, Jacob L., Debost, Jean-Christophe P. G., Morton, Sarah U., Wigdor, Emilie M., Heyne, Henrike O., Lal, Dennis, Howrigan, Daniel P., Bloemendal, Alex, Larsen, Janne T., Kosmicki, Jack A., Weiner, Daniel J., Homsy, Jason, Seidman, Jonathan G., Seidman, Christine E., Agerbo, Esben, McGrath, John J., Mortensen, Preben Bo, Petersen, Liselotte, Daly, Mark J., and Robinson, Elise B.

Published
2019
Full Text
View/download PDF

28. 38. COMMON AND RARE GENETIC RISK FACTORS FOR SCHIZOPHRENIA AT CHROMOSOME 22Q INDUCE CONVERGENT, DISPERSED CHANGES IN GENE EXPRESSION

Author

Nadig, Ajay, primary, Tegtmeyer, Matthew, additional, Weiner, Daniel J., additional, Ling, Emi, additional, Gordon, Aaron, additional, O'Connor, Luke J., additional, Aryee, Martin J., additional, Bearden, Carrie E., additional, Geschwind, Daniel, additional, McCarroll, Steve A., additional, Nehme, Ralda, additional, and Robinson, Elise B., additional

Published
2022
Full Text
View/download PDF

29. Principled distillation of multidimensional UK Biobank data reveals insights into the correlated human phenome

Author

Carey, Caitlin E., primary, Shafee, Rebecca, additional, Elliott, Amanda, additional, Palmer, Duncan S., additional, Compitello, John, additional, Kanai, Masahiro, additional, Abbott, Liam, additional, Schultz, Patrick, additional, Karczewski, Konrad J., additional, Bryant, Samuel C., additional, Cusick, Caroline M., additional, Churchhouse, Claire, additional, Howrigan, Daniel P., additional, King, Daniel, additional, Smith, George Davey, additional, Wedow, Robbee, additional, Neale, Benjamin M., additional, Walters, Raymond K., additional, and Robinson, Elise B., additional

Published
2022
Full Text
View/download PDF

32. Polygenic risk for schizophrenia and measured domains of cognition in individuals with psychosis and controls

Author

Shafee, Rebecca, Nanda, Pranav, Padmanabhan, Jaya L., Tandon, Neeraj, Alliey-Rodriguez, Ney, Kalapurakkel, Sreeja, Weiner, Daniel J., Gur, Raquel E., Keefe, Richard S. E., Hill, Scot K., Bishop, Jeffrey R., Clementz, Brett A., Tamminga, Carol A., Gershon, Elliot S., Pearlson, Godfrey D., Keshavan, Matcheri S., Sweeney, John A., McCarroll, Steven A., and Robinson, Elise B.

Published
2018
Full Text
View/download PDF

33. Brief Report: No Association between Parental Age and Extreme Social-Communicative Autistic Traits in the General Population

Author

Robinson, Elise B., Munir, Kerim, McCormick, Marie C., Koenen, Karestan C., and Santangelo, Susan L.

Abstract

This is the first investigation of the relationship between parental age and extreme social-communicative autistic traits in the general population. The parents of 5,246 children in the Avon Longitudinal Study of Parents and Children (ALSPAC) completed the Social and Communication Disorders Checklist (SCDC). The association between parental age and SCDC scores was assessed in the full sample and among high scoring individuals (e.g. top 5%, 1%). There was no association between parental age and social-communicative autistic traits in the general population. Neither maternal nor paternal age was associated with extreme scores. These findings suggest that advanced parental age does not confer increased risk for extreme social and communication impairment assessed quantitatively. (Contains 2 figures.)

Published
2011
Full Text
View/download PDF

34. Stability of Autistic Traits in the General Population: Further Evidence for a Continuum of Impairment

Author

Robinson, Elise B., Munir, Kerim, and Munafo, Marcus R.

Abstract

Objective: This study investigated the developmental course of autistic traits in a nationally representative sample of subjects 7 to 13 years of age. Method: The parents of 6,539 children in the Avon Longitudinal Study of Parents and Children completed the Social and Communication Disorders Checklist at ages 7, 10, and 13. The phenotypic progression of autistic traits was assessed in the full sample and in high-scoring individuals (e.g., top 10%, 5%). Gender, IQ, and overall behavior difficulties were examined as potentially relevant influences on autistic trait trajectories. Results: Autistic traits were highly stable in the general population overall and in the high-scoring groups. In the full sample, there was no change in mean Social and Communication Disorders Checklist scores for female subjects ages 7 to 13 (p = 0.43). Scores for male subjects decreased slightly, but significantly, on the order of 0.1 standard deviations (p less than 0.001). There was no mean change in parent-rated autistic traits within any of the high-scoring groups. IQ was not related to phenotypic progression; high parent-rated behavior problems predicted slight improvement in Social and Communication Disorders Checklist scores over the course of the study period in high-scoring individuals (p less than 0.01). Conclusions: These findings suggest that autistic traits are highly stable in the general population, even in individuals with the highest concentrations of autism-like behaviors. Phenotypic stability is consistent with expectations for individuals with autism spectrum disorders, providing further support for a phenomenologic continuum across the clinical threshold. Moreover, the gap between female and male risk for autistic symptomology is consistent over time. (Contains 3 tables and 2 figures.)

Published
2011
Full Text
View/download PDF

37. Assessing the utility of electronic measures as a proxy for cognitive ability

Author

Levy, Tess, primary, Britvan, Bari, additional, Grosman, Hannah, additional, Giserman‐Kiss, Ivy, additional, Meyering, Kristin, additional, Weissman, Jordana, additional, Halpern, Danielle, additional, Zweifach, Jessica, additional, Trelles, M. Pilar, additional, Foss‐Feig, Jennifer H., additional, Kolevzon, Alexander, additional, Sanders, Stephan J., additional, Robinson, Elise B., additional, Buxbaum, Joseph D., additional, Bishop, Somer, additional, and Siper, Paige M., additional

Published
2022
Full Text
View/download PDF

39. List of Contributors

Author

Addy, Nii A., primary, Almasy, Laura, additional, Almli, Lynn M., additional, AuYong, Nicholas, additional, Bai, Hanwen, additional, Barrera, Daniel J., additional, Bearden, Carrie E., additional, Berry, James D., additional, Bettcher, Brianne M., additional, Bevan, Carolyn, additional, Blangero, John, additional, Bordelon, Yvette M., additional, Brown, Jesse A., additional, Bulik, Cynthia M., additional, Clark, Victoria E., additional, Corvin, Aiden, additional, Curran, Joanne E., additional, Cuthbert, Bruce N., additional, D'Gama, Alissa M., additional, Daly, Mark J., additional, Dhindsa, Ryan S., additional, Dölen, Gül, additional, Evans, Andrew, additional, Freimer, Nelson B., additional, Geschwind, Daniel H., additional, Geschwind, Michael D., additional, Glahn, David C., additional, Goldstein, David B., additional, Greally, John M., additional, Greicius, Michael, additional, Grinberg, Lea T., additional, Günel, Jennifer M., additional, Günel, Murat, additional, Gur, Raquel E., additional, Gur, Ruben C., additional, Haase, Claudia M., additional, Heinsen, Helmut, additional, Hibar, Derrek P., additional, Hodgson, Karen, additional, Hooli, Basavaraj, additional, Hrvoj-Mihic, Branka, additional, Jacob, Louis, additional, Jahanshad, Neda, additional, Jamuar, Saumya S., additional, Keener, Adrienne M., additional, Knowles, Emma E.M., additional, Lammel, Stephan, additional, Lee, Suzee E., additional, Levenson, Robert W., additional, Li, Mingfeng, additional, Lins, Mauro F.C., additional, Lowenstein, Daniel H., additional, Mahlios, Joshua, additional, Malenka, Robert C., additional, Mason, Christopher E., additional, Mathias, Samuel R., additional, Mendez, Mario F., additional, Merikangas, Kathleen R., additional, Merikangas, Alison K., additional, Mignot, Emmanuel, additional, Mocellin, Ramon, additional, Muhle, Rebecca A., additional, Muotri, Alysson R., additional, Naasan, Georges, additional, Nagarajan, Srikantan S., additional, Neale, Benjamin M., additional, Negraes, Priscilla D., additional, Nestler, Eric J., additional, Ollila, Hanna M., additional, Olvera, Rene L., additional, Paholpak, Pongsatorn, additional, Parikshak, Neelroop N., additional, Perlis, Roy H., additional, Pochareddy, Sirisha, additional, Portera-Cailliau, Carlos, additional, Pouratian, Nader, additional, Purcell, Shaun M., additional, Rabinovici, Gil D., additional, Ranasinghe, Kamalini G., additional, Ratti, Elena, additional, Reed, Hannah E., additional, Ressler, Kerry J., additional, Robinson, Elise B., additional, Sanders, Stephan J., additional, Schadt, Eric E., additional, Schonhaut, Daniel R., additional, Sebat, Jonathan, additional, Seeley, William W., additional, Semendeferi, Katerina, additional, Sestan, Nenad, additional, Shapiro, Kevin A., additional, Sherr, Elliot H., additional, Silbereis, John C., additional, Solecki, Wojciech B., additional, Spinelli, Edoardo G., additional, State, Matthew W., additional, Stein, Jason L., additional, Stuber, Garret D., additional, Sturm, Virginia E., additional, Sullivan, Patrick F., additional, Tanzi, Rudolph E., additional, Tempini, Maria L.G., additional, Theofilas, Panos, additional, Thompson, Paul M., additional, Trujillo, Cleber A., additional, Velakoulis, Dennis, additional, Vossel, Keith A., additional, Walsh, Christopher A., additional, Walterfang, Mark, additional, Wingo, Aliza P., additional, Yao, Nailin, additional, Yokoyama, Jennifer S., additional, Youngblood, Mark W., additional, Zandi, Peter, additional, and Zhu, Ying, additional

Published
2016
Full Text
View/download PDF

41. A framework for the interpretation of de novo mutation in human disease

Author

Samocha, Kaitlin E, Robinson, Elise B, Sanders, Stephan J, Stevens, Christine, Sabo, Aniko, McGrath, Lauren M, Kosmicki, Jack A, Rehnström, Karola, Mallick, Swapan, Kirby, Andrew, Wall, Dennis P, MacArthur, Daniel G, Gabriel, Stacey B, DePristo, Mark, Purcell, Shaun M, Palotie, Aarno, Boerwinkle, Eric, Buxbaum, Joseph D, Cook, Jr, Edwin H, Gibbs, Richard A, Schellenberg, Gerard D, Sutcliffe, James S, Devlin, Bernie, Roeder, Kathryn, Neale, Benjamin M, and Daly, Mark J

Published
2014
Full Text
View/download PDF

42. 47. GENE DISCOVERY FROM EXOME SEQUENCING IN AUTISM AND COMPARISON TO DEVELOPMENTAL DELAY AND SCHIZOPHRENIA

Author

Satterstrom, F. Kyle, primary, Fu, Jack, additional, Peng, Minshi, additional, Brand, Harrison, additional, Collins, Ryan L., additional, Dong, Shan, additional, Børglum, Anders D., additional, Robinson, Elise B., additional, Cutler, David J., additional, Buxbaum, Joseph D., additional, Daly, Mark J., additional, Roeder, Kathryn, additional, Devlin, Bernie, additional, Sanders, Stephan J., additional, and Talkowski, Michael E., additional

Published
2021
Full Text
View/download PDF

47. Identification of shared and differentiating genetic risk for autism spectrum disorder, attention deficit hyperactivity disorder and case subgroups

Author

Mattheisen, Manuel, primary, Grove, Jakob, additional, Als, Thomas D, additional, Martin, Joanna, additional, Voloudakis, Georgios, additional, Meier, Sandra, additional, Demontis, Ditte, additional, Bendl, Jaroslav, additional, Walters, Raymond, additional, Carey, Caitlin E, additional, Rosengren, Anders, additional, Strom, Nora, additional, Hauberg, Mads Engel, additional, Zeng, Biao, additional, Hoffman, Gabriel, additional, Bybjerg-Grauholm, Jonas, additional, Bækvad-Hansen, Marie, additional, Agerbo, Esben, additional, Cormand, Bru, additional, Nordentoft, Merete, additional, Werge, Thomas, additional, Mors, Ole, additional, Hougaard, David M, additional, Buxbaum, Joseph D, additional, Faraone, Stephen V, additional, Franke, Barbara, additional, Dalsgaard, Søren, additional, Mortensen, Preben B, additional, Robinson, Elise B, additional, Roussos, Panos, additional, Neale, Benjamin M, additional, Daly, Mark J, additional, and Børglum, Anders D, additional

Published
2021
Full Text
View/download PDF

50. Genetic correlates of phenotypic heterogeneity in autism

Author

Warrier, Varun, Zhang, Xinhe, Reed, Patrick, Havdahl, Alexandra, Moore, Tyler M., Cliquet, Freddy, Leblond, Claire S., Rolland, Thomas, Rosengren, Anders, Caceres, Antonia San Jose, Hayward, Hannah, Crawley, Daisy, Faulkner, Jessica, Sabet, Jessica, Ellis, Claire, Oakley, Bethany, Loth, Eva, Charman, Tony, Murphy, Declan, Holt, Rosemary, Waldman, Jack, Upadhyay, Jessica, Gunby, Nicola, Lai, Meng-Chuan, Renouf, Gwilym, Ruigrok, Amber, Taylor, Emily, Ziauddeen, Hisham, Deakin, Julia, di Bruttopilo, Sara Ambrosino, van Dijk, Sarai, Rijks, Yvonne, Koops, Tabitha, Douma, Miriam, Spaan, Alyssia, Selten, Iris, Steffers, Maarten, van Themaat, Anna Ver Loren, Bast, Nico, Baumeister, Sarah, O’Dwyer, Larry, Bours, Carsten, Rausch, Annika, von Rhein, Daniel, Cornelissen, Ineke, de Bruin, Yvette, Graauwmans, Maartje, Kostrzewa, Elzbieta, Cauvet, Elodie, Tammimies, Kristiina, Sitnikow, Rouslan, Dumas, Guillaume, Kim, Yang-Min, Bourgeron, Thomas, Hougaard, David M., Bybjerg-Grauholm, Jonas, Werge, Thomas, Mortensen, Preben Bo, Mors, Ole, Nordentoft, Merete, Adhya, Dwaipayan, Alamanza, Armandina, Allison, Carrie, Garvey, Isabelle, Parsons, Tracey, Smith, Paula, Tsompanidis, Alex, Burton, Graham J., Heazell, Alexander E. P., Gabis, Lidia V., Biron-Shental, Tal, Lancaster, Madeline A., Srivastava, Deepak P., Mill, Jonathan, Rowitch, David H., Hurles, Matthew E., Geschwind, Daniel H., Børglum, Anders D., Robinson, Elise B., Grove, Jakob, Martin, Hilary C., Baron-Cohen, Simon, University of Cambridge [UK] (CAM), Lovisenberg Diakonale Sykehus - Lovisenberg Diaconal Hospital [Oslo], Norwegian Institute of Public Health [Oslo] (NIPH), University of Oslo (UiO), University of Pennsylvania [Philadelphia], Children’s Hospital of Philadelphia (CHOP ), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen University Hospital, The Wellcome Trust Sanger Institute [Cambridge], University of California [Los Angeles] (UCLA), University of California, Aarhus University [Aarhus], Broad Institute [Cambridge], Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT), Massachusetts General Hospital [Boston], Harvard T.H. Chan School of Public Health, V.W. is funded by St. Catharine’s College, Cambridge. This study was funded by grants to SBC from the Medical Research Council, the Wellcome Trust, the Autism Research Trust, the Templeton World Charity Foundation, and to T.B. from the Institut Pasteur, the CNRS, The Bettencourt-Schueller and the Cognacq-Jay Foundations, the APHP and the Université de Paris. SBC was funded by the Autism Research Trust, the Wellcome Trust, the Templeton World Charitable Foundation, and the NIHR Biomedical Research Centre in Cambridge, during the period of this work. The Medical Research Council (MRC) funded the Cambridge Autism Research Database (CARD) that made this study possible. SBC also received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 777394. The JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and AUTISM SPEAKS, Autistica, SFARI. His research was also supported by the National Institute of Health Research (NIHR) Applied Research Collaboration East of England (ARC EoE) programme. T.M.M. is supported by U.S. National Institutes of Mental Health (NIMH) grant MH117014. The views expressed are those of the authors, and not necessarily those of the NIHR, NHS or Department of Health and Social Care. We acknowledge with gratitude the generous support of Drs Dennis and Mireille Gillings in strengthening the collaboration between S.B.-C. and T.B., and between Cambridge University and the Institut Pasteur. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The AIMS-2-TRIALS LEAP receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and AUTISM SPEAKS, Autistica, SFARI. A full list of the authors and affiliations in the AIMS-2-TRIALS LEAP group is provided in the Supplementary Information. The iPSYCH team was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724 and R248-2017-2003), NIMH (1U01MH109514-01 to ADB) and the universities and university hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to ADB). We thank Jonathan Sebat for sharing the de novo variant calls in the SPARK and SSC datasets., Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Warrier, Varun [0000-0003-4532-8571], Havdahl, Alexandra [0000-0002-9268-0423], Moore, Tyler M [0000-0002-1384-0151], Rosengren, Anders [0000-0002-6682-1288], Hurles, Matthew E [0000-0002-2333-7015], Geschwind, Daniel H [0000-0003-2896-3450], Børglum, Anders D [0000-0001-8627-7219], Grove, Jakob [0000-0003-2284-5744], Martin, Hilary C [0000-0002-4454-9084], Bourgeron, Thomas [0000-0001-8164-9220], Baron-Cohen, Simon [0000-0001-9217-2544], Apollo - University of Cambridge Repository, University of Pennsylvania, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of California (UC), Harvard University-Massachusetts Institute of Technology (MIT), and S.B.-C. received funding from the Wellcome Trust (214322\Z\18\Z). For the purpose of open access, we have applied a CC BY public copyright licence to any author accepted manuscript version arising from this submission. S.B.-C. also received funding from the Autism Centre of Excellence, the SFARI, the Templeton World Charitable Fund, the MRC and the National Institute for Health Research Cambridge Biomedical Research Centre. The research was supported by the National Institute for Health Research Applied Research Collaboration East of England. Any views expressed are those of the author(s) and not necessarily those of the funder. Some of the results leading to this publication have received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 777394 for the project AIMS-2-TRIALS. This joint undertaking receives support from the European Union’s Horizon 2020 research and innovation program and the EFPIA and Autism Speaks, Autistica and the SFARI. V.W. is funded by St. Catharine’s College, Cambridge. T.B. has received funding from the Institut Pasteur, the CNRS, the Bettencourt–Schueller and the Cognacq–Jay Foundations, the APHP and the Université de Paris Cité. We acknowledge with gratitude the generous support of D. and M. Gillings in strengthening the collaboration between S.B.-C. and T.B. and between Cambridge University and the Institut Pasteur. The iPSYCH team was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724 and R248-2017-2003), the NIMH (1U01MH109514-01 to A.D.B.) and the universities and university hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to A.D.B.). We thank J. Sebat for sharing the de novo variant calls in the SPARK and SSC datasets. We are grateful to all families at the participating SSC sites as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren and E. Wijsman). We are grateful to all families in the SPARK study, the SPARK clinical sites and SPARK staff.

Subjects
Male, Autism Spectrum Disorder, CHILDREN, behavioral disciplines and activities, Developmental psychology, Correlation, 03 medical and health sciences, Nonverbal communication, AGE, Cognition, 0302 clinical medicine, Intellectual Disability, mental disorders, Genetics, medicine, Humans, Limited evidence, GENOME-WIDE ASSOCIATION, Autistic Disorder, Association (psychology), COMMON, SPECTRUM DISORDER, 030304 developmental biology, RISK, ARCHITECTURE, 0303 health sciences, IDENTIFICATION, [SCCO.NEUR]Cognitive science/Neuroscience, medicine.disease, Educational attainment, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, DE-NOVO MUTATIONS, Adaptive behaviour, Schizophrenia, Autism, Female, SIMONS SIMPLEX COLLECTION, Psychology, 030217 neurology & neurosurgery
Abstract

Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440, Funder: Templeton World Charity Foundation (Templeton World Charity Foundation, Inc.); doi: https://doi.org/10.13039/501100011730, The substantial phenotypic heterogeneity in autism limits our understanding of its genetic etiology. To address this gap, here we investigated genetic differences between autistic individuals (nmax = 12,893) based on core and associated features of autism, co-occurring developmental disabilities and sex. We conducted a comprehensive factor analysis of core autism features in autistic individuals and identified six factors. Common genetic variants were associated with the core factors, but de novo variants were not. We found that higher autism polygenic scores (PGS) were associated with lower likelihood of co-occurring developmental disabilities in autistic individuals. Furthermore, in autistic individuals without co-occurring intellectual disability (ID), autism PGS are overinherited by autistic females compared to males. Finally, we observed higher SNP heritability for autistic males and for autistic individuals without ID. Deeper phenotypic characterization will be critical in determining how the complex underlying genetics shape cognition, behavior and co-occurring conditions in autism.

Published
2020

Catalog

Books, media, physical & digital resources
See catalog results