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Bridget A. Fernandez

Bio: Bridget A. Fernandez is an academic researcher from Memorial University of Newfoundland. The author has contributed to research in topics: Autism & Autism spectrum disorder. The author has an hindex of 52, co-authored 83 publications receiving 17047 citations. Previous affiliations of Bridget A. Fernandez include University of Oxford & Health Sciences Centre.


Papers
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Journal ArticleDOI
Silvia De Rubeis1, Xin-Xin He2, Arthur P. Goldberg1, Christopher S. Poultney1, Kaitlin E. Samocha3, A. Ercument Cicek2, Yan Kou1, Li Liu2, Menachem Fromer3, Menachem Fromer1, R. Susan Walker4, Tarjinder Singh5, Lambertus Klei6, Jack A. Kosmicki3, Shih-Chen Fu1, Branko Aleksic7, Monica Biscaldi8, Patrick Bolton9, Jessica M. Brownfeld1, Jinlu Cai1, Nicholas G. Campbell10, Angel Carracedo11, Angel Carracedo12, Maria H. Chahrour3, Andreas G. Chiocchetti, Hilary Coon13, Emily L. Crawford10, Lucy Crooks5, Sarah Curran9, Geraldine Dawson14, Eftichia Duketis, Bridget A. Fernandez15, Louise Gallagher16, Evan T. Geller17, Stephen J. Guter18, R. Sean Hill3, R. Sean Hill19, Iuliana Ionita-Laza20, Patricia Jiménez González, Helena Kilpinen, Sabine M. Klauck21, Alexander Kolevzon1, Irene Lee22, Jing Lei2, Terho Lehtimäki, Chiao-Feng Lin17, Avi Ma'ayan1, Christian R. Marshall4, Alison L. McInnes23, Benjamin M. Neale24, Michael John Owen25, Norio Ozaki7, Mara Parellada26, Jeremy R. Parr27, Shaun Purcell1, Kaija Puura, Deepthi Rajagopalan4, Karola Rehnström5, Abraham Reichenberg1, Aniko Sabo28, Michael Sachse, Stephen Sanders29, Chad M. Schafer2, Martin Schulte-Rüther30, David Skuse31, David Skuse22, Christine Stevens24, Peter Szatmari32, Kristiina Tammimies4, Otto Valladares17, Annette Voran33, Li-San Wang17, Lauren A. Weiss29, A. Jeremy Willsey29, Timothy W. Yu19, Timothy W. Yu3, Ryan K. C. Yuen4, Edwin H. Cook18, Christine M. Freitag, Michael Gill16, Christina M. Hultman34, Thomas Lehner35, Aarno Palotie36, Aarno Palotie24, Aarno Palotie3, Gerard D. Schellenberg17, Pamela Sklar1, Matthew W. State29, James S. Sutcliffe10, Christopher A. Walsh19, Christopher A. Walsh3, Stephen W. Scherer4, Michael E. Zwick37, Jeffrey C. Barrett5, David J. Cutler37, Kathryn Roeder2, Bernie Devlin6, Mark J. Daly24, Mark J. Daly3, Joseph D. Buxbaum1 
13 Nov 2014-Nature
TL;DR: Using exome sequencing, it is shown 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 of < 0.05, plus a set of 107 genes strongly enriched for those likely to affect risk (FDR < 0.30).
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.

2,228 citations

Journal ArticleDOI
Dalila Pinto1, Alistair T. Pagnamenta2, Lambertus Klei3, Richard Anney4  +178 moreInstitutions (46)
15 Jul 2010-Nature
TL;DR: The genome-wide characteristics of rare (<1% frequency) copy number variation in ASD are analysed using dense genotyping arrays to reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
Abstract: The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

1,919 citations

Journal ArticleDOI
TL;DR: The results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility.
Abstract: Structural variation (copy number variation [CNV] including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder (ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in ∼7% and ∼2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at ∼1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.

1,716 citations

Journal ArticleDOI
Dalila Pinto1, Elsa Delaby2, Elsa Delaby3, Elsa Delaby4, Daniele Merico5, Mafalda Barbosa1, Alison K. Merikangas6, Lambertus Klei7, Bhooma Thiruvahindrapuram5, Xiao Xu1, Robert Ziman5, Zhuozhi Wang5, Jacob A. S. Vorstman8, Ann P. Thompson9, Regina Regan10, Regina Regan11, Marion Pilorge2, Marion Pilorge4, Marion Pilorge3, Giovanna Pellecchia5, Alistair T. Pagnamenta12, Bárbara Oliveira13, Bárbara Oliveira14, Christian R. Marshall5, Tiago R. Magalhaes11, Tiago R. Magalhaes10, Jennifer K. Lowe15, Jennifer L. Howe5, Anthony J. Griswold16, John R. Gilbert16, Eftichia Duketis17, Beth A. Dombroski18, Maretha de Jonge8, Michael L. Cuccaro16, Emily L. Crawford19, Catarina Correia14, Catarina Correia13, Judith Conroy20, Inȇs C. Conceição14, Inȇs C. Conceição13, Andreas G. Chiocchetti17, Jillian P. Casey10, Jillian P. Casey11, Guiqing Cai1, Christelle Cabrol3, Christelle Cabrol2, Christelle Cabrol4, Nadia Bolshakova6, Elena Bacchelli21, Richard Anney6, Steven Gallinger5, Michelle Cotterchio22, Graham Casey23, Lonnie Zwaigenbaum24, Kerstin Wittemeyer25, Kirsty Wing12, Simon Wallace12, Herman van Engeland8, Ana Tryfon26, Susanne Thomson19, Latha Soorya27, Bernadette Rogé, Wendy Roberts5, Fritz Poustka17, Susana Mouga28, Nancy J. Minshew7, L. Alison McInnes29, Susan G. McGrew19, Catherine Lord30, Marion Leboyer, Ann Le Couteur31, Alexander Kolevzon1, Patricia Jiménez González, Suma Jacob32, Suma Jacob33, Richard Holt12, Stephen J. Guter33, Jonathan Green, Andrew Green10, Andrew Green11, Christopher Gillberg34, Bridget A. Fernandez35, Frederico Duque28, Richard Delorme, Geraldine Dawson36, Pauline Chaste, Cátia Café, Sean Brennan6, Thomas Bourgeron37, Patrick Bolton38, Patrick Bolton39, Sven Bölte17, Raphael Bernier40, Gillian Baird39, Anthony J. Bailey12, Evdokia Anagnostou5, Joana Almeida, Ellen M. Wijsman40, Veronica J. Vieland41, Astrid M. Vicente14, Astrid M. Vicente13, Gerard D. Schellenberg18, Margaret A. Pericak-Vance16, Andrew D. Paterson5, Jeremy R. Parr31, Guiomar Oliveira28, John I. Nurnberger42, Anthony P. Monaco43, Anthony P. Monaco12, Elena Maestrini21, Sabine M. Klauck44, Hakon Hakonarson18, Jonathan L. Haines19, Daniel H. Geschwind15, Christine M. Freitag17, Susan E. Folstein16, Sean Ennis11, Sean Ennis10, Hilary Coon45, Agatino Battaglia, Peter Szatmari9, James S. Sutcliffe19, Joachim Hallmayer46, Michael Gill6, Edwin H. Cook33, Joseph D. Buxbaum1, Bernie Devlin7, Louise Gallagher6, Catalina Betancur2, Catalina Betancur3, Catalina Betancur4, Stephen W. Scherer5 
TL;DR: For example, the authors 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.
Abstract: 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.

833 citations

Journal ArticleDOI
TL;DR: Food fortification with folic acid was associated with a significant reduction in the rate of neural-tube defects in Canada, and the decrease was greatest in areas in which the baseline rate was high.
Abstract: Results A total of 2446 subjects with neural-tube defects were recorded among 1.9 million births. The prevalence of neural-tube defects decreased from 1.58 per 1000 births before fortification to 0.86 per 1000 births during the full-fortification period, a 46% reduction (95% confidence interval, 40 to 51). The magnitude of the decrease was proportional to the prefortification baseline rate in each province, and geographical differences almost disappeared after fortification began. The observed reduction in rate was greater for spina bifida (a decrease of 53%) than for anencephaly and encephalocele (decreases of 38% and 31%, respectively). Conclusions Food fortification with folic acid was associated with a significant reduction in the rate of neural-tube defects in Canada. The decrease was greatest in areas in which the baseline rate was high.

735 citations


Cited by
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01 Feb 2015
TL;DR: In this article, the authors describe the integrative analysis of 111 reference human epigenomes generated as part of the NIH Roadmap Epigenomics Consortium, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression.
Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

4,409 citations

Journal ArticleDOI
TL;DR: These and other strategies are providing researchers and clinicians a variety of tools to probe genomes in greater depth, leading to an enhanced understanding of how genome sequence variants underlie phenotype and disease.
Abstract: Since the completion of the human genome project in 2003, extraordinary progress has been made in genome sequencing technologies, which has led to a decreased cost per megabase and an increase in the number and diversity of sequenced genomes. An astonishing complexity of genome architecture has been revealed, bringing these sequencing technologies to even greater advancements. Some approaches maximize the number of bases sequenced in the least amount of time, generating a wealth of data that can be used to understand increasingly complex phenotypes. Alternatively, other approaches now aim to sequence longer contiguous pieces of DNA, which are essential for resolving structurally complex regions. These and other strategies are providing researchers and clinicians a variety of tools to probe genomes in greater depth, leading to an enhanced understanding of how genome sequence variants underlie phenotype and disease.

3,096 citations

Journal ArticleDOI
TL;DR: This article identified 255 loci across the human genome that contain genomic imbalances among unrelated individuals, and revealed that half of these regions overlap with genes, and many coincide with segmental duplications or gaps in human genome assembly.
Abstract: We identified 255 loci across the human genome that contain genomic imbalances among unrelated individuals. Twenty-four variants are present in > 10% of the individuals that we examined. Half of these regions overlap with genes, and many coincide with segmental duplications or gaps in the human genome assembly. This previously unappreciated heterogeneity may underlie certain human phenotypic variation and susceptibility to disease and argues for a more dynamic human genome structure.

2,937 citations

Journal ArticleDOI
TL;DR: The remarkable range of discoveriesGWASs has facilitated in population and complex-trait genetics, the biology of diseases, and translation toward new therapeutics are reviewed.
Abstract: Application of the experimental design of genome-wide association studies (GWASs) is now 10 years old (young), and here we review the remarkable range of discoveries it has facilitated in population and complex-trait genetics, the biology of diseases, and translation toward new therapeutics. We predict the likely discoveries in the next 10 years, when GWASs will be based on millions of samples with array data imputed to a large fully sequenced reference panel and on hundreds of thousands of samples with whole-genome sequencing data.

2,669 citations

Journal ArticleDOI
01 Jun 2017-Cell
TL;DR: The core Wnt/β-catenin signaling pathway is described, how it controls stem cells, and contributes to disease, and strategies for Wnt-based therapies are discussed.

2,663 citations