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Neale, Benjamin

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Neale

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Benjamin

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Neale, Benjamin
Author's Publications: search.filters.isAuthorOfPublication.93faedab-8ebe-4922-a542-29dca650577c

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    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.
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    Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection
    (Springer Science and Business Media LLC, 2021-06) Zekavat, Seyedeh M.; Lin, Shu-Hong; Bick, Alexander G.; Liu, Aoxing; Paruchuri, Kaavya; Wang, Chen; Uddin, Md Mesbah; Ye, Yixuan; Yu, Zhaolong; Liu, Xiaoxi; Kamatani, Yoichiro; Bhattacharya, Romit; Pirruccello, James; Pampana, Akhil; Loh, Po-Ru; Kohli, Puja; McCarroll, Steven; Kiryluk, Krzysztof; Neale, Benjamin; Ionita-Laza, Iuliana; Engels, Eric; Brown, Derek W.; Smoller, Jordan; Green, Robert; Karlson, Elizabeth; Lebo, Matthew; Ellinor, Patrick; Weiss, Scott; Daly, Mark; Terao, Chikashi; Zhao, Hongyu; Ebert, Benjamin; Reilly, Muredach; Ganna, Andrea; Machiela, Mitchell; Genovese, Giulio; Natarajan, Pradeep
    The burden of mosaic chromosomal alterations in blood-derived DNA, a type of clonal hematopoiesis, is associated with an increased risk for diverse types of infections, including sepsis and pneumonia. Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 x 10(-7)), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 x 10(-28)), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 x 10(-15)), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 x 10(-9)) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 x 10(-4)). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.
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    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.
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    A framework for the interpretation of de novo mutation in human disease
    (2014) Samocha, Kaitlin E.; Robinson, Elise; Sanders, Stephan J.; Stevens, Christine; Sabo, Aniko; McGrath, Lauren M.; Kosmicki, Jack; Rehnström, Karola; Mallick, Swapan; Kirby, Andrew; Wall, Dennis P.; MacArthur, Daniel; Gabriel, Stacey B.; dePristo, Mark; Purcell, Shaun M.; Palotie, Aarno; Boerwinkle, Eric; Buxbaum, Joseph D.; Cook, Edwin H.; Gibbs, Richard A.; Schellenberg, Gerard D.; Sutcliffe, James S.; Devlin, Bernie; Roeder, Kathryn; Neale, Benjamin; Daly, Mark
    Spontaneously arising (‘de novo’) mutations play an important role in medical genetics. For diseases with extensive locus heterogeneity – such as autism spectrum disorders (ASDs) – the signal from de novo mutations (DNMs) is distributed across many genes, making it difficult to distinguish disease-relevant mutations from background variation. We provide a statistical framework for the analysis of DNM excesses per gene and gene set by calibrating a model of de novo mutation. We applied this framework to DNMs collected from 1,078 ASD trios and – while affirming a significant role for loss-of-function (LoF) mutations – found no excess of de novo LoF mutations in cases with IQ above 100, suggesting that the role of DNMs in ASD may reside in fundamental neurodevelopmental processes. We also used our model to identify ~1,000 genes that are significantly lacking functional coding variation in non-ASD samples and are enriched for de novo LoF mutations identified in ASD cases.
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    Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles
    (2014) Goldstein, Jacqueline I; Jarskog, L Fredrik; Hilliard, Chris; Alfirevic, Ana; Duncan, Laramie; Fourches, Denis; Huang, Hailiang; Lek, Monkol; Neale, Benjamin; Ripke, Stephan; Shianna, Kevin; Szatkiewicz, Jin P; Tropsha, Alexander; van den Oord, Edwin JCG; Cascorbi, Ingolf; Dettling, Michael; Gazit, Ephraim; Goff, Donald C; Holden, Arthur L; Kelly, Deanna L; Malhotra, Anil K; Nielsen, Jimmi; Pirmohamed, Munir; Rujescu, Dan; Werge, Thomas; Levy, Deborah; Josiassen, Richard C; Kennedy, James L; Lieberman, Jeffrey A; Daly, Mark; Sullivan, Patrick F
    Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the risk of clozapine-induced agranulocytosis/granulocytopenia (CIAG), a severe adverse drug reaction occurring in up to 1% of treated individuals. Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine. Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing. We find that two loci in the major histocompatibility complex are independently associated with CIAG: a single amino acid in HLA-DQB1 (126Q) (P=4.7×10−14, odds ratio, OR=0.19, 95% CI 0.12–0.29) and an amino acid change in the extracellular binding pocket of HLA-B (158T) (P=6.4×10−10, OR=3.3, 95% CI 2.3–4.9). These associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG.
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    The genetic architecture of pediatric cognitive abilities in the Philadelphia Neurodevelopmental Cohort
    (2014) Robinson, Elise; Kirby, Andrew; Ruparel, Kosha; Yang, Jian; McGrath, Lauren; Anttila, Verneri; Neale, Benjamin; Merikangas, Kathleen; Lehner, Thomas; Sleiman, Patrick M.A.; Daly, Mark; Gur, Ruben; Gur, Raquel; Hakonarson, Hakon
    The objective of this analysis was to examine the genetic architecture of diverse cognitive abilities in children and adolescents, including the magnitude of common genetic effects and patterns of shared and unique genetic influences. Subjects included 3,689 members of the Philadelphia Neurodevelopmental Cohort, a general population sample of ages 8-21 years who completed an extensive battery of cognitive tests. We used genome-wide complex trait analysis (GCTA) to estimate the SNP-based heritability of each domain, as well as the genetic correlation between all domains that showed significant genetic influence. Several of the individual domains suggested strong influence of common genetic variants (e.g. reading ability, h2g=0.43, p=4e-06; emotion identification, h2g=0.36, p=1e-05; verbal memory, h2g=0.24, p=0.005). The genetic correlations highlighted trait domains that are candidates for joint interrogation in future genetic studies (e.g. language reasoning and spatial reasoning, r(g)=0.72, p=0.007). These results can be used to structure future genetic and neuropsychiatric investigations of diverse cognitive abilities.
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    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.
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    Comparison of Methods That Use Whole Genome Data to Estimate the Heritability and Genetic Architecture of Complex Traits
    (Springer Science and Business Media LLC, 2018-05) Evans, Luke M.; Tahmasbi, Rasool; Vrieze, Scott I.; Abecasis, Gonçalo R.; Das, Sayantan; Gazal, Steven; Bjelland, Douglas W.; de Candia, Teresa R.; Goddard, Michael E.; Neale, Benjamin; Yang, Jian; Visscher, Peter M.; Keller, Matthew C.
    Multiple methods have been developed to estimate narrow-sense heritability, h2, using single nucleotide polymorphisms (SNPs) in unrelated individuals. However, a comprehensive evaluation of these methods has not yet been performed, leading to confusion and discrepancy in the literature. We present the most thorough and realistic comparison of these methods to date. We used thousands of real whole-genome sequences to simulate phenotypes under varying genetic architectures and confounding variables, and we used array, imputed, or whole genome sequence SNPs to obtain 'SNP-heritability' estimates. We show that SNP-heritability can be highly sensitive to assumptions about the frequencies, effect sizes, and levels of linkage disequilibrium of underlying causal variants, but that methods that bin SNPs according to minor allele frequency and linkage disequilibrium are less sensitive to these assumptions across a wide range of genetic architectures and possible confounding factors. These findings provide guidance for best practices and proper interpretation of published estimates.
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    Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population
    (Public Library of Science, 2018) Rivas, Manuel A.; Avila, Brandon E.; Koskela, Jukka; Huang, Hailiang; Stevens, Christine; Pirinen, Matti; Haritunians, Talin; Neale, Benjamin; Kurki, Mitja; Ganna, Andrea; Graham, Daniel; Glaser, Benjamin; Peter, Inga; Atzmon, Gil; Barzilai, Nir; Levine, Adam P.; Schiff, Elena; Pontikos, Nikolas; Weisburd, Ben; Lek, Monkol; Karczewski, Konrad; Bloom, Jonathan; Minikel, Eric; Petersen, Britt-Sabina; Beaugerie, Laurent; Seksik, Philippe; Cosnes, Jacques; Schreiber, Stefan; Bokemeyer, Bernd; Bethge, Johannes; Heap, Graham; Ahmad, Tariq; Plagnol, Vincent; Segal, Anthony W.; Targan, Stephan; Turner, Dan; Saavalainen, Paivi; Farkkila, Martti; Kontula, Kimmo; Palotie, Aarno; Brant, Steven R.; Duerr, Richard H.; Silverberg, Mark S.; Rioux, John D.; Weersma, Rinse K.; Franke, Andre; Jostins, Luke; Anderson, Carl A.; Barrett, Jeffrey C.; MacArthur, Daniel; Jalas, Chaim; Sokol, Harry; Xavier, Ramnik; Pulver, Ann; Cho, Judy H.; McGovern, Dermot P. B.; Daly, Mark
    As part of a broader collaborative network of exome sequencing studies, we developed a jointly called data set of 5,685 Ashkenazi Jewish exomes. We make publicly available a resource of site and allele frequencies, which should serve as a reference for medical genetics in the Ashkenazim (hosted in part at https://ibd.broadinstitute.org, also available in gnomAD at http://gnomad.broadinstitute.org). We estimate that 34% of protein-coding alleles present in the Ashkenazi Jewish population at frequencies greater than 0.2% are significantly more frequent (mean 15-fold) than their maximum frequency observed in other reference populations. Arising via a well-described founder effect approximately 30 generations ago, this catalog of enriched alleles can contribute to differences in genetic risk and overall prevalence of diseases between populations. As validation we document 148 AJ enriched protein-altering alleles that overlap with "pathogenic" ClinVar alleles (table available at https://github.com/macarthur-lab/clinvar/blob/master/output/clinvar.tsv), including those that account for 10–100 fold differences in prevalence between AJ and non-AJ populations of some rare diseases, especially recessive conditions, including Gaucher disease (GBA, p.Asn409Ser, 8-fold enrichment); Canavan disease (ASPA, p.Glu285Ala, 12-fold enrichment); and Tay-Sachs disease (HEXA, c.1421+1G>C, 27-fold enrichment; p.Tyr427IlefsTer5, 12-fold enrichment). We next sought to use this catalog, of well-established relevance to Mendelian disease, to explore Crohn's disease, a common disease with an estimated two to four-fold excess prevalence in AJ. We specifically attempt to evaluate whether strong acting rare alleles, particularly protein-truncating or otherwise large effect-size alleles, enriched by the same founder-effect, contribute excess genetic risk to Crohn's disease in AJ, and find that ten rare genetic risk factors in NOD2 and LRRK2 are enriched in AJ (p < 0.005), including several novel contributing alleles, show evidence of association to CD. Independently, we find that genomewide common variant risk defined by GWAS shows a strong difference between AJ and non-AJ European control population samples (0.97 s.d. higher, p<10−16). Taken together, the results suggest coordinated selection in AJ population for higher CD risk alleles in general. The results and approach illustrate the value of exome sequencing data in case-control studies along with reference data sets like ExAC (sites VCF available via FTP at ftp.broadinstitute.org/pub/ExAC_release/release0.3/) to pinpoint genetic variation that contributes to variable disease predisposition across populations.
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    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.