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1.
Nat Commun ; 15(1): 1755, 2024 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-38409228

RESUMEN

Nearly two hundred common-variant depression risk loci have been identified by genome-wide association studies (GWAS). However, the impact of rare coding variants on depression remains poorly understood. Here, we present whole-exome sequencing analyses of depression with seven different definitions based on survey, questionnaire, and electronic health records in 320,356 UK Biobank participants. We showed that the burden of rare damaging coding variants in loss-of-function intolerant genes is significantly associated with risk of depression with various definitions. We compared the rare and common genetic architecture across depression definitions by genetic correlation and showed different genetic relationships between definitions across common and rare variants. In addition, we demonstrated that the effects of rare damaging coding variant burden and polygenic risk score on depression risk are additive. The gene set burden analyses revealed overlapping rare genetic variant components with developmental disorder, autism, and schizophrenia. Our study provides insights into the contribution of rare coding variants, separately and in conjunction with common variants, on depression with various definitions and their genetic relationships with neurodevelopmental disorders.


Asunto(s)
Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Secuenciación del Exoma , Bancos de Muestras Biológicas , Depresión/genética , Biobanco del Reino Unido
2.
Immunotherapy ; 15(15): 1257-1273, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37661910

RESUMEN

Background: Soft tissue and bone sarcomas are rare entities, hence, standardized therapeutic strategies are difficult to assess. Materials & methods: Immunohistochemistry was performed on 68 sarcoma samples to assess the expression of PD-1, PD-L1, IDO and CD70 in different tumor compartments and molecular analysis was performed to assess microsatellite instability status. Results: PD-1/PD-L1, IDO and CD70 pathways are at play in the immune evasion of sarcomas in general. Soft tissue sarcomas more often show an inflamed phenotype compared with bone sarcomas. Specific histologic sarcoma types show high expression levels of different markers. Finally, this is the first presentation of a microsatellite instability-high Kaposi sarcoma. Discussion/conclusion: Immune evasion occurs in sarcomas. Specific histologic types might benefit from immunotherapy, for which further investigation is needed.


Sarcomas of the soft tissue and bone are rare cancers. When these cancers spread to other parts of the body, it is hard to find good treatments. Recently, doctors have been using a new type of treatment called immunotherapy to fight several types of cancer. Immunotherapy works by getting one's body's own defense cells to attack the cancer cells. Unfortunately, immunotherapy does not work well for sarcomas and we do not know why. This study was designed to determine if there are certain mechanisms in these tumors that help the cancer cells to hide from defense cells. Determining how to change these mechanisms could make immunotherapy a better treatment for sarcomas in the future.


Asunto(s)
Neoplasias Óseas , Osteosarcoma , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Receptor de Muerte Celular Programada 1 , Evasión Inmune , Antígeno B7-H1/genética , Inestabilidad de Microsatélites , Sarcoma/genética , Sarcoma/terapia , Ligando CD27
3.
Nat Genet ; 55(6): 927-938, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37231097

RESUMEN

Compelling evidence suggests that human cognitive function is strongly influenced by genetics. Here, we conduct a large-scale exome study to examine whether rare protein-coding variants impact cognitive function in the adult population (n = 485,930). We identify eight genes (ADGRB2, KDM5B, GIGYF1, ANKRD12, SLC8A1, RC3H2, CACNA1A and BCAS3) that are associated with adult cognitive function through rare coding variants with large effects. Rare genetic architecture for cognitive function partially overlaps with that of neurodevelopmental disorders. In the case of KDM5B we show how the genetic dosage of one of these genes may determine the variability of cognitive, behavioral and molecular traits in mice and humans. We further provide evidence that rare and common variants overlap in association signals and contribute additively to cognitive function. Our study introduces the relevance of rare coding variants for cognitive function and unveils high-impact monogenic contributions to how cognitive function is distributed in the normal adult population.


Asunto(s)
Variación Genética , Trastornos del Neurodesarrollo , Humanos , Adulto , Animales , Ratones , Predisposición Genética a la Enfermedad , Fenotipo , Cognición , Proteínas Portadoras/genética , Proteínas Nucleares/genética
4.
OTO Open ; 6(4): 2473974X221134106, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36311182

RESUMEN

Objective: To implement a quality improvement initiative to achieve an institutional targeted discharge summary distribution metric of 50% within 48 hours of patient discharge from hospital within an academic tertiary care otolaryngology-head and neck surgery department. Methods: A pre- and postintervention study was conducted. Process mapping was performed. Interventions included education and engagement, implementation of auto-authentication (distribution immediately following transcription without review by the most responsible physician), and audit and feedback. The percentage of discharge summaries dictated with the auto-authentication code was evaluated. Process measures were collected for 12 months pre- and postimplementation. Balancing measures included workload and revisions to auto-authenticated notes. Analysis included summary statistics, statistical process control charting, and unpaired t tests. Results: The mean ± SD percentage of discharge summaries distributed within 48 hours increased from 19% ± 6.4% preintervention to 54% ± 20% postintervention (P < .0001). Seventy-four percent of discharge summaries were dictated via the auto-authentication code. The target metric was met in 71% of discharges with the auto-authentication codes as compared with 26% with non-auto-authentication. The interventions did not result in any change to perceived workload, and the incidence of auto-authentication revisions was <1%. The results were sustained with an increase of 72% the following quarter. For fiscal year 2021-2022, performance remained sustained with an 85% completion rate. Discussion: Our surgical department exceeded and sustained the targeted metric for timely discharge summary distribution using a quality improvement approach. Implications for Practice: Timely distribution of discharge summaries optimizes patients' transitions of care and can be achieved through stakeholder education and engagement, auto-authentication, and audit with feedback.

5.
Nat Aging ; 2(4): 289-294, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-37117740

RESUMEN

Genetic predisposition has been shown to contribute substantially to the age at which we die. Genome-wide association studies (GWASs) have linked more than 20 loci to phenotypes related to human lifespan1. However, little is known about how lifespan is impacted by gene loss of function. Through whole-exome sequencing of 352,338 UK Biobank participants of European ancestry, we assessed the relevance of protein-truncating variant (PTV) gene burden on individual and parental survival. We identified four exome-wide significant (P < 4.2 × 10-7) human lifespan genes, BRCA1, BRCA2, ATM and TET2. Gene and gene-set, PTV-burden, phenome-wide association studies support known roles of these genes in cancer to impact lifespan at the population level. The TET2 PTV burden was associated with a lifespan through somatic mutation events presumably due to clonal hematopoiesis. The overlap between PTV burden and common variant-based lifespan GWASs was modest, underscoring the value of exome sequencing in well-powered biobank cohorts to complement GWASs for identifying genes underlying complex traits.


Asunto(s)
Estudio de Asociación del Genoma Completo , Longevidad , Humanos , Longevidad/genética , Proteínas/genética , Predisposición Genética a la Enfermedad/genética , Fenotipo
6.
Nat Commun ; 12(1): 6411, 2021 11 05.
Artículo en Inglés | MEDLINE | ID: mdl-34741066

RESUMEN

Complex traits are characterized by multiple genes and variants acting simultaneously on a phenotype. However, studying the contribution of individual pairs of genes to complex traits has been challenging since human genetics necessitates very large population sizes, while findings from model systems do not always translate to humans. Here, we combine genetics with combinatorial RNAi (coRNAi) to systematically test for pairwise additive effects (AEs) and genetic interactions (GIs) between 30 lipid genome-wide association studies (GWAS) genes. Gene-based burden tests from 240,970 exomes show that in carriers with truncating mutations in both, APOB and either PCSK9 or LPL ("human double knock-outs") plasma lipid levels change additively. Genetics and coRNAi identify overlapping AEs for 12 additional gene pairs. Overlapping GIs are observed for TOMM40/APOE with SORT1 and NCAN. Our study identifies distinct gene pairs that modulate plasma and cellular lipid levels primarily via AEs and nominates putative drug target pairs for improved lipid-lowering combination therapies.


Asunto(s)
Estudio de Asociación del Genoma Completo/métodos , Proproteína Convertasa 9/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/genética , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Apolipoproteínas B/genética , Apolipoproteínas B/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Humanos , Lipoproteína Lipasa/genética , Lipoproteína Lipasa/metabolismo , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales/genética , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales/metabolismo , Neurocano/genética , Neurocano/metabolismo , Proproteína Convertasa 9/genética
7.
Nat Genet ; 53(6): 861-868, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-34083789

RESUMEN

Microglia, the tissue-resident macrophages of the central nervous system (CNS), play critical roles in immune defense, development and homeostasis. However, isolating microglia from humans in large numbers is challenging. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single-cell and bulk RNA sequencing, we identify how age, sex and clinical pathology influence microglia gene expression and which genetic variants have microglia-specific functions using expression quantitative trait loci (eQTL) mapping. We follow up one of our findings using a human induced pluripotent stem cell-based macrophage model to fine-map a candidate causal variant for Alzheimer's disease at the BIN1 locus. Our study provides a population-scale transcriptional map of a critically important cell for human CNS development and disease.


Asunto(s)
Regulación de la Expresión Génica , Microglía/metabolismo , Transcripción Genética , Enfermedad de Alzheimer/genética , Humanos , Modelos Genéticos , Sitios de Carácter Cuantitativo/genética , Análisis de Secuencia de ARN , Análisis de la Célula Individual
9.
Nat Genet ; 53(3): 392-402, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33589840

RESUMEN

Genome-wide association studies have discovered numerous genomic loci associated with Alzheimer's disease (AD); yet the causal genes and variants are incompletely identified. We performed an updated genome-wide AD meta-analysis, which identified 37 risk loci, including new associations near CCDC6, TSPAN14, NCK2 and SPRED2. Using three SNP-level fine-mapping methods, we identified 21 SNPs with >50% probability each of being causally involved in AD risk and others strongly suggested by functional annotation. We followed this with colocalization analyses across 109 gene expression quantitative trait loci datasets and prioritization of genes by using protein interaction networks and tissue-specific expression. Combining this information into a quantitative score, we found that evidence converged on likely causal genes, including the above four genes, and those at previously discovered AD loci, including BIN1, APH1B, PTK2B, PILRA and CASS4.


Asunto(s)
Enfermedad de Alzheimer/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Mapeo Cromosómico , Proteínas del Citoesqueleto/genética , Expresión Génica , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Desequilibrio de Ligamiento , Microglía/fisiología , Proteínas Oncogénicas/genética , Polimorfismo de Nucleótido Simple , Mapas de Interacción de Proteínas/genética , Sitios de Carácter Cuantitativo , Factores de Riesgo , Tetraspaninas/genética
10.
PLoS Genet ; 17(1): e1009224, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33417599

RESUMEN

Discovering drugs that efficiently treat brain diseases has been challenging. Genetic variants that modulate the expression of potential drug targets can be utilized to assess the efficacy of therapeutic interventions. We therefore employed Mendelian Randomization (MR) on gene expression measured in brain tissue to identify drug targets involved in neurological and psychiatric diseases. We conducted a two-sample MR using cis-acting brain-derived expression quantitative trait loci (eQTLs) from the Accelerating Medicines Partnership for Alzheimer's Disease consortium (AMP-AD) and the CommonMind Consortium (CMC) meta-analysis study (n = 1,286) as genetic instruments to predict the effects of 7,137 genes on 12 neurological and psychiatric disorders. We conducted Bayesian colocalization analysis on the top MR findings (using P<6x10-7 as evidence threshold, Bonferroni-corrected for 80,557 MR tests) to confirm sharing of the same causal variants between gene expression and trait in each genomic region. We then intersected the colocalized genes with known monogenic disease genes recorded in Online Mendelian Inheritance in Man (OMIM) and with genes annotated as drug targets in the Open Targets platform to identify promising drug targets. 80 eQTLs showed MR evidence of a causal effect, from which we prioritised 47 genes based on colocalization with the trait. We causally linked the expression of 23 genes with schizophrenia and a single gene each with anorexia, bipolar disorder and major depressive disorder within the psychiatric diseases and 9 genes with Alzheimer's disease, 6 genes with Parkinson's disease, 4 genes with multiple sclerosis and two genes with amyotrophic lateral sclerosis within the neurological diseases we tested. From these we identified five genes (ACE, GPNMB, KCNQ5, RERE and SUOX) as attractive drug targets that may warrant follow-up in functional studies and clinical trials, demonstrating the value of this study design for discovering drug targets in neuropsychiatric diseases.


Asunto(s)
Enfermedad de Alzheimer/genética , Descubrimiento de Drogas , Predisposición Genética a la Enfermedad , Transcriptoma/genética , Enfermedad de Alzheimer/tratamiento farmacológico , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/genética , Trastorno Bipolar/patología , Encéfalo/metabolismo , Encéfalo/patología , Estudio de Asociación del Genoma Completo , Humanos , Análisis de la Aleatorización Mendeliana , Terapia Molecular Dirigida , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/patología , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo/genética , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Esquizofrenia/patología
11.
Nat Genet ; 52(10): 1122-1131, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32895551

RESUMEN

The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium is widespread in naïve phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes ( https://www.epigraphdb.org/pqtl/ ). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.


Asunto(s)
Proteínas Sanguíneas/genética , Predisposición Genética a la Enfermedad , Análisis de la Aleatorización Mendeliana , Proteoma/genética , Estudio de Asociación del Genoma Completo , Humanos , Fenotipo , Polimorfismo de Nucleótido Simple/genética
12.
JAMA Neurol ; 77(10): 1288-1298, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32568366

RESUMEN

Importance: Genetic studies of Alzheimer disease have focused on the clinical or pathologic diagnosis as the primary outcome, but little is known about the genetic basis of the preclinical phase of the disease. Objective: To examine the underlying genetic basis for brain amyloidosis in the preclinical phase of Alzheimer disease. Design, Setting, and Participants: In the first stage of this genetic association study, a meta-analysis was conducted using genetic and imaging data acquired from 6 multicenter cohort studies of healthy older individuals between 1994 and 2019: the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study, the Berkeley Aging Cohort Study, the Wisconsin Registry for Alzheimer's Prevention, the Biomarkers of Cognitive Decline Among Normal Individuals cohort, the Baltimore Longitudinal Study of Aging, and the Alzheimer Disease Neuroimaging Initiative, which included Alzheimer disease and mild cognitive impairment. The second stage was designed to validate genetic observations using pathologic and clinical data from the Religious Orders Study and Rush Memory and Aging Project. Participants older than 50 years with amyloid positron emission tomographic (PET) imaging data and DNA from the 6 cohorts were included. The largest cohort, the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study (n = 3154), was the PET screening cohort used for a secondary prevention trial designed to slow cognitive decline associated with brain amyloidosis. Six smaller, longitudinal cohort studies (n = 1160) provided additional amyloid PET imaging data with existing genetic data. The present study was conducted from March 29, 2019, to February 19, 2020. Main Outcomes and Measures: A genome-wide association study of PET imaging amyloid levels. Results: From the 4314 analyzed participants (age, 52-96 years; 2478 participants [57%] were women), a novel locus for amyloidosis was noted within RBFOX1 (ß = 0.61, P = 3 × 10-9) in addition to APOE. The RBFOX1 protein localized around plaques, and reduced expression of RBFOX1 was correlated with higher amyloid-ß burden (ß = -0.008, P = .002) and worse cognition (ß = 0.007, P = .006) during life in the Religious Orders Study and Rush Memory and Aging Project cohort. Conclusions and Relevance: RBFOX1 encodes a neuronal RNA-binding protein known to be expressed in neuronal tissues and may play a role in neuronal development. The findings of this study suggest that RBFOX1 is a novel locus that may be involved in the pathogenesis of Alzheimer disease.


Asunto(s)
Enfermedad de Alzheimer/genética , Amiloidosis/genética , Encéfalo , Estudios de Asociación Genética/métodos , Variación Genética/genética , Factores de Empalme de ARN/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Amiloidosis/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Estudios de Cohortes , Diagnóstico Precoz , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síntomas Prodrómicos
13.
PLoS Genet ; 14(12): e1007833, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30507971

RESUMEN

Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disease characterised by progressive destruction of intrahepatic bile ducts. The strongest genetic association is with HLA-DQA1*04:01, but at least three additional independent HLA haplotypes contribute to susceptibility. We used dense single nucleotide polymorphism (SNP) data in 2861 PBC cases and 8514 controls to impute classical HLA alleles and amino acid polymorphisms using state-of-the-art methodologies. We then demonstrated through stepwise regression that association in the HLA region can be largely explained by variation at five separate amino acid positions. Three-dimensional modelling of protein structures and calculation of electrostatic potentials for the implicated HLA alleles/amino acid substitutions demonstrated a correlation between the electrostatic potential of pocket P6 in HLA-DP molecules and the HLA-DPB1 alleles/amino acid substitutions conferring PBC susceptibility/protection, highlighting potential new avenues for future functional investigation.


Asunto(s)
Antígenos HLA/genética , Cirrosis Hepática Biliar/genética , Cirrosis Hepática Biliar/inmunología , Complejo Mayor de Histocompatibilidad , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Genes MHC Clase II , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Antígenos HLA/química , Antígenos HLA-C/genética , Cadenas beta de HLA-DP/química , Cadenas beta de HLA-DP/genética , Cadenas alfa de HLA-DQ/genética , Cadenas beta de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Humanos , Modelos Genéticos , Modelos Moleculares , Polimorfismo de Nucleótido Simple , Conformación Proteica , Análisis de Regresión , Electricidad Estática
14.
Bioinformatics ; 34(15): 2538-2545, 2018 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-29579179

RESUMEN

Motivation: Most genetic variants implicated in complex diseases by genome-wide association studies (GWAS) are non-coding, making it challenging to understand the causative genes involved in disease. Integrating external information such as quantitative trait locus (QTL) mapping of molecular traits (e.g. expression, methylation) is a powerful approach to identify the subset of GWAS signals explained by regulatory effects. In particular, expression QTLs (eQTLs) help pinpoint the responsible gene among the GWAS regions that harbor many genes, while methylation QTLs (mQTLs) help identify the epigenetic mechanisms that impact gene expression which in turn affect disease risk. In this work, we propose multiple-trait-coloc (moloc), a Bayesian statistical framework that integrates GWAS summary data with multiple molecular QTL data to identify regulatory effects at GWAS risk loci. Results: We applied moloc to schizophrenia (SCZ) and eQTL/mQTL data derived from human brain tissue and identified 52 candidate genes that influence SCZ through methylation. Our method can be applied to any GWAS and relevant functional data to help prioritize disease associated genes. Availability and implementation: moloc is available for download as an R package (https://github.com/clagiamba/moloc). We also developed a web site to visualize the biological findings (icahn.mssm.edu/moloc). The browser allows searches by gene, methylation probe and scenario of interest. Supplementary information: Supplementary data are available at Bioinformatics online.


Asunto(s)
Mapeo Cromosómico/métodos , Epigénesis Genética , Genómica/métodos , Sitios de Carácter Cuantitativo , Programas Informáticos , Transcriptoma , Teorema de Bayes , Encéfalo/metabolismo , Metilación de ADN , Epigenómica/métodos , Perfilación de la Expresión Génica/métodos , Estudio de Asociación del Genoma Completo/métodos , Humanos , Esquizofrenia/genética
15.
Gut ; 67(8): 1517-1524, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-28779025

RESUMEN

OBJECTIVE: Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. DESIGN: We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients-obtained using the Illumina immunochip-with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. RESULTS: We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10-9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. CONCLUSION: We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.


Asunto(s)
Colangitis Esclerosante/genética , Colangitis Esclerosante/patología , Polimorfismo de Nucleótido Simple/genética , Trombospondinas/genética , Adulto , Colangitis Esclerosante/mortalidad , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales
16.
Nat Genet ; 49(3): 325-331, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28092683

RESUMEN

Collecting cases for case-control genetic association studies can be time-consuming and expensive. In some situations (such as studies of late-onset or rapidly lethal diseases), it may be more practical to identify family members of cases. In randomly ascertained cohorts, replacing cases with their first-degree relatives enables studies of diseases that are absent (or nearly absent) in the cohort. We refer to this approach as genome-wide association study by proxy (GWAX) and apply it to 12 common diseases in 116,196 individuals from the UK Biobank. Meta-analysis with published genome-wide association study summary statistics replicated established risk loci and yielded four newly associated loci for Alzheimer's disease, eight for coronary artery disease and five for type 2 diabetes. In addition to informing disease biology, our results demonstrate the utility of association mapping without directly observing cases. We anticipate that GWAX will prove useful in future genetic studies of complex traits in large population cohorts.


Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de la Arteria Coronaria/genética , Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad/genética , Estudios de Casos y Controles , Genoma Humano/genética , Estudio de Asociación del Genoma Completo/métodos , Humanos , Riesgo
18.
Nat Genet ; 49(2): 269-273, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27992413

RESUMEN

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (rG = 0.04) (P = 2.55 × 10-15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10-15). Our study represents a substantial advance in understanding of the genetics of PSC.


Asunto(s)
Colangitis Esclerosante/genética , Enfermedades Inflamatorias del Intestino/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Alelos , Colitis Ulcerosa/genética , Estudio de Asociación del Genoma Completo/métodos , Humanos , Polimorfismo de Nucleótido Simple/genética , ARN Mensajero/genética , Factores de Riesgo
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