Person:
Howrigan, Daniel

Profile Picture

Email Address

AA Acceptance Date

Birth Date

Research Projects

Organizational Units

Job Title

Last Name

Howrigan

First Name

Daniel

Name

Howrigan, Daniel
Author's Publications: search.filters.isAuthorOfPublication.8ad27e67-f02b-428b-80fc-dc2a706a6ec8

Search Results

Now showing 1 - 7 of 7
  • No Thumbnail Available
    Publication
    Identification of common genetic risk variants for autism spectrum disorder
    (Springer Science and Business Media LLC, 2019-02-25) Grove, Jakob; Ripke, Stephan; Als, Thomas D.; Mattheisen, Manuel; Walters, Raymond; 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; Goldstein, Jacqueline; Hansen, Christine S.; Hauberg, Mads Engel; Hollegaard, Mads V.; Hope, Sigrun; Howrigan, Daniel; Huang, Hailiang; Hultman, Christina M.; Klei, Lambertus; Maller, Julian; Martin, Joanna; Martin, Alicia R.; Moran, Jennifer; Nyegaard, Mette; Nærland, Terje; Palmer, Duncan; Palotie, Aarno; Pedersen, Carsten Bøcker; Pedersen, Marianne Giørtz; Poterba, Timothy; Pourcain, Beate St; Poulsen, Jesper Buchhave; Qvist, Per; Rehnström, Karola; Reichenberg, Abraham; Reichert, Jennifer; Robinson, Elise; 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; Daly, Mark; Børglum, Anders D.
    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 ASD cases and 27,969 controls that identifies five genome-wide significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), seven additional loci shared with other traits are identified at equally strict significance levels. Dissecting the polygenic architecture we find both quantitative and qualitative polygenic heterogeneity across ASD subtypes, in contrast to what is typically seen in other complex disorders. 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, just as it has been in a broad range of important psychiatric and diverse medical phenotypes.
  • No Thumbnail Available
    Publication
    Exome Sequencing in Schizophrenia-Affected Parent–offspring Trios Reveals Risk Conferred by Protein-Coding De Novo Mutations
    (Springer Science and Business Media LLC, 2020-01-13) Howrigan, Daniel; Rose, Samuel A.; Samocha, Kaitlin E.; Fromer, Menachem; Cerrato, Felecia; Chen, Wei J.; Churchhouse, Claire; Chambert, Kimberly; Chandler, Sharon D.; Daly, Mark; Dumont, Ashley; Genovese, Giulio; Hwu, Hai-Gwo; Laird, Nan; Kosmicki, Jack; Moran, Jennifer L.; Singh, Tarjinder; McCarroll, Steven; Faraone, Stephen V.; Glatt, Stephen J.; Tsuang, Ming; Neale, Benjamin
    Protein-coding de novo mutations (DNMs) are significant risk factors in many neurodevelopmental disorders, whereas association with schizophrenia (SCZ) risk thus far has been modest. We analyze whole-exome sequence from 1,695 SCZ affected trios along with DNMs from 1,077 published SCZ trios to better understand their contribution to SCZ risk. Among 2,772 SCZ probands, exome-wide DNM burden remains modest. Gene set analyses reveal that SCZ DNMs are significantly concentrated in genes either highly brain expressed, under strong evolutionary constraint, and/or overlap with genes identified in other neurodevelopmental disorders. No single gene surpasses exome-wide significance, however sixteen genes are recurrently hit by protein-truncating DNMs, a 3.15-fold higher rate than the mutation model expectation (permuted 95% CI=1-10 genes, permuted p=3e-5). Overall, DNMs explain only a small fraction of SCZ risk, and larger samples are needed to identify individual risk genes, as coding variation across many genes confer risk for SCZ in the population.
  • Thumbnail Image
    Publication
    Analysis of protein-coding genetic variation in 60,706 humans
    (2016) Lek, Monkol; Karczewski, Konrad; Minikel, Eric; Samocha, Kaitlin E.; Banks, Eric; Fennell, Timothy; O'Donnell-Luria, Anne H; Ware, James S; Hill, Andrew J; Cummings, Beryl; Tukiainen, Taru; Birnbaum, Daniel P; Kosmicki, Jack; Duncan, Laramie E; Estrada, Karol; Zhao, Fengmei; Zou, James; Pierce-Hoffman, Emma; Berghout, Joanne; Cooper, David N; Deflaux, Nicole; DePristo, Mark; Do, Ron; Flannick, Jason; Fromer, Menachem; Gauthier, Laura; Goldstein, Jackie; Gupta, Namrata; Howrigan, Daniel; Kiezun, Adam; Kurki, Mitja; Moonshine, Ami Levy; Natarajan, Pradeep; Orozco, Lorena; Peloso, Gina M; Poplin, Ryan; Rivas, Manuel A; Ruano-Rubio, Valentin; Rose, Samuel A; Ruderfer, Douglas M; Shakir, Khalid; Stenson, Peter D; Stevens, Christine; Thomas, Brett P; Tiao, Grace; Tusie-Luna, Maria T; Weisburd, Ben; Won, Hong-Hee; Yu, Dongmei; Altshuler, David; Ardissino, Diego; Boehnke, Michael; Danesh, John; Donnelly, Stacey; Elosua, Roberto; Florez, Jose; Gabriel, Stacey B; Getz, Gad; Glatt, Stephen J; Hultman, Christina M; Kathiresan, Sekar; Laakso, Markku; McCarroll, Steven; McCarthy, Mark I; McGovern, Dermot; McPherson, Ruth; Neale, Benjamin; Palotie, Aarno; Purcell, Shaun M; Saleheen, Danish; Scharf, Jeremiah; Sklar, Pamela; Sullivan, Patrick F; Tuomilehto, Jaakko; Tsuang, Ming T; Watkins, Hugh C; Wilson, James G; Daly, Mark; MacArthur, Daniel
    Summary Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. We describe the aggregation and analysis of high-quality exome (protein-coding region) sequence data for 60,706 individuals of diverse ethnicities generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of truncating variants with 72% having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human “knockout” variants in protein-coding genes.
  • Thumbnail Image
    Publication
    Heterogeneous contribution of microdeletions in the development of common generalised and focal epilepsies
    (BMJ Publishing Group, 2017) Pérez-Palma, Eduardo; Helbig, Ingo; Klein, Karl Martin; Anttila, Verneri; Horn, Heiko; Reinthaler, Eva Maria; Gormley, Padhraig; Ganna, Andrea; Byrnes, Andrea; Pernhorst, Katharina; Toliat, Mohammad R; Saarentaus, Elmo; Howrigan, Daniel; Hoffman, Per; Miquel, Juan Francisco; De Ferrari, Giancarlo V; Nürnberg, Peter; Lerche, Holger; Zimprich, Fritz; Neubauer, Bern A; Becker, Albert J; Rosenow, Felix; Perucca, Emilio; Zara, Federico; Weber, Yvonne G; Lal, Dennis
    Background: Microdeletions are known to confer risk to epilepsy, particularly at genomic rearrangement ‘hotspot’ loci. However, microdeletion burden not overlapping these regions or within different epilepsy subtypes has not been ascertained. Objective: To decipher the role of microdeletions outside hotspots loci and risk assessment by epilepsy subtype. Methods: We assessed the burden, frequency and genomic content of rare, large microdeletions found in a previously published cohort of 1366 patients with genetic generalised epilepsy (GGE) in addition to two sets of additional unpublished genome-wide microdeletions found in 281 patients with rolandic epilepsy (RE) and 807 patients with adult focal epilepsy (AFE), totalling 2454 cases. Microdeletions were assessed in a combined and subtype-specific approaches against 6746 controls. Results: When hotspots are considered, we detected an enrichment of microdeletions in the combined epilepsy analysis (adjusted p=1.06×10−6,OR 1.89, 95% CI 1.51 to 2.35). Epilepsy subtype-specific analyses showed that hotspot microdeletions in the GGE subgroup contribute most of the overall signal (adjusted p=9.79×10−12, OR 7.45, 95% CI 4.20–13.5). Outside hotspots , microdeletions were enriched in the GGE cohort for neurodevelopmental genes (adjusted p=9.13×10−3,OR 2.85, 95% CI 1.62–4.94). No additional signal was observed for RE and AFE. Still, gene-content analysis identified known (NRXN1, RBFOX1 and PCDH7) and novel (LOC102723362) candidate genes across epilepsy subtypes that were not deleted in controls. Conclusions: Our results show a heterogeneous effect of recurrent and non-recurrent microdeletions as part of the genetic architecture of GGE and a minor contribution in the aetiology of RE and AFE.
  • Thumbnail Image
    Publication
    Refining the role of de novo protein truncating variants in neurodevelopmental disorders using population reference samples
    (2017) Kosmicki, Jack; Samocha, Kaitlin E.; Howrigan, Daniel; Sanders, Stephan J.; Slowikowski, Kamil; Lek, Monkol; Karczewski, Konrad; Cutler, David J.; Devlin, Bernie; Roeder, Kathryn; Buxbaum, Joseph D.; Neale, Benjamin; MacArthur, Daniel; Wall, Dennis P.; Robinson, Elise; Daly, Mark
    Recent research has uncovered a significant role for de novo variation in neurodevelopmental disorders. Using aggregated data from 9246 families with autism spectrum disorder, intellectual disability, or developmental delay, we show ~1/3 of de novo variants are independently observed 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 use a loss-of-function (LoF)-intolerance metric, pLI, to identify a subset of LoF-intolerant genes that contain 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; though the strongest de novo impacted genes contribute little to this, suggesting the excess of inherited risk resides 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.
  • Thumbnail Image
    Publication
    Ultra-rare disruptive and damaging mutations influence educational attainment in the general population
    (2016) Ganna, Andrea; Genovese, Giulio; Howrigan, Daniel; Byrnes, Andrea; Kurki, Mitja; Zekavat, Seyedeh M.; Whelan, Christopher W.; Kals, Mart; Nivard, Michel G.; Bloemendal, Alex; Bloom, Jonathan M.; Goldstein, Jacqueline I.; Poterba, Timothy; Seed, Cotton; Handsaker, Robert; Natarajan, Pradeep; Mägi, Reedik; Gage, Diane; Robinson, Elise; Metspalu, Andres; Salomaa, Veikko; Suvisaari, Jaana; Purcell, Shaun M.; Sklar, Pamela; Kathiresan, Sekar; Daly, Mark; McCarroll, Steven; Sullivan, Patrick F.; Palotie, Aarno; Esko, Tõnu; Hultman, Christina; Neale, Benjamin
    Disruptive and damaging ultra-rare variants (URVs) in highly constrained (HC) genes are enriched in individuals with neurodevelopmental disorders. In the general population, this class of variants was associated with a decrease in years of education (YOE; −3.1 months; P-value=3.3×10−8). This effect was stronger among high brain-expressed genes and explained more YOE variance than pathogenic copy number variation, but less than common variants. Disruptive and damaging URVs in HC genes influence the determinants of YOE in the general population.
  • Thumbnail Image
    Publication
    Runs of Homozygosity Implicate Autozygosity as a Schizophrenia Risk Factor
    (Public Library of Science, 2012) Keller, Matthew C.; Simonson, Matthew A.; Ripke, Stephan; Gejman, Pablo V.; Lencz, Todd; Levinson, Douglas F.; Sullivan, Patrick F.; Neale, Benjamin; Howrigan, Daniel; Lee, Sang Hong
    Autozygosity occurs when two chromosomal segments that are identical from a common ancestor are inherited from each parent. This occurs at high rates in the offspring of mates who are closely related (inbreeding), but also occurs at lower levels among the offspring of distantly related mates. Here, we use runs of homozygosity in genome-wide SNP data to estimate the proportion of the autosome that exists in autozygous tracts in 9,388 cases with schizophrenia and 12,456 controls. We estimate that the odds of schizophrenia increase by \(\sim 17 \% \) for every \(1 \% \) increase in genome-wide autozygosity. This association is not due to one or a few regions, but results from many autozygous segments spread throughout the genome, and is consistent with a role for multiple recessive or partially recessive alleles in the etiology of schizophrenia. Such a bias towards recessivity suggests that alleles that increase the risk of schizophrenia have been selected against over evolutionary time.