Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
1.
Mol Psychiatry ; 26(8): 4496-4510, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-32015465

RESUMO

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10-6). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.


Assuntos
Síndrome de DiGeorge , Transtornos Psicóticos , Esquizofrenia , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Síndrome de DiGeorge/genética , Humanos , Esquizofrenia/genética
2.
Pac Symp Biocomput ; 29: 247-260, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38160284

RESUMO

A single gene can produce multiple transcripts with distinct molecular functions. Rare-variant association tests often aggregate all coding variants across individual genes, without accounting for the variants' presence or consequence in resulting transcript isoforms. To evaluate the utility of transcript-aware variant sets, rare predicted loss-of-function (pLOF) variants were aggregated for 17,035 protein-coding genes using 55,558 distinct transcript-specific variant sets. These sets were tested for their association with 728 circulating proteins and 188 quantitative phenotypes across 406,921 individuals in the UK Biobank. The transcript-specific approach resulted in larger estimated effects of pLOF variants decreasing serum cis-protein levels compared to the gene-based approach (pbinom ≤ 2x10-16). Additionally, 251 quantitative trait associations were identified as being significant using the transcript-specific approach but not the gene-based approach, including PCSK5 transcript ENST00000376752 and standing height (transcript-specific statistic, P = 1.3x10-16, effect = 0.7 SD decrease; gene-based statistic, P = 0.02, effect = 0.05 SD decrease) and LDLR transcript ENST00000252444 and apolipoprotein B (transcript-specific statistic, P = 5.7x10-20, effect = 1.0 SD increase; gene-based statistic, P = 3.0x10-4, effect = 0.2 SD increase). This approach demonstrates the importance of considering the effect of pLOFs on specific transcript isoforms when performing rare-variant association studies.


Assuntos
Bancos de Espécimes Biológicos , Biobanco do Reino Unido , Humanos , Biologia Computacional , Fenótipo , Isoformas de Proteínas/genética
3.
Nat Commun ; 13(1): 4319, 2022 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-35896531

RESUMO

Identifying genetic variants associated with lower waist-to-hip ratio can reveal new therapeutic targets for abdominal obesity. We use exome sequences from 362,679 individuals to identify genes associated with waist-to-hip ratio adjusted for BMI (WHRadjBMI), a surrogate for abdominal fat that is causally linked to type 2 diabetes and coronary heart disease. Predicted loss of function (pLOF) variants in INHBE associate with lower WHRadjBMI and this association replicates in data from AMP-T2D-GENES. INHBE encodes a secreted protein, the hepatokine activin E. In vitro characterization of the most common INHBE pLOF variant in our study, indicates an in-frame deletion resulting in a 90% reduction in secreted protein levels. We detect associations with lower WHRadjBMI for variants in ACVR1C, encoding an activin receptor, further highlighting the involvement of activins in regulating fat distribution. These findings highlight activin E as a potential therapeutic target for abdominal obesity, a phenotype linked to cardiometabolic disease.


Assuntos
Diabetes Mellitus Tipo 2 , Subunidades beta de Inibinas/genética , Receptores de Ativinas Tipo I/genética , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/genética , Humanos , Obesidade/genética , Obesidade Abdominal/genética , Relação Cintura-Quadril
4.
Sci Adv ; 8(23): eabn3328, 2022 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-35675391

RESUMO

In 1995, journalist Gary Taubes published an article in Science titled "Epidemiology faces its limits," which questioned the utility of nonrandomized epidemiologic research and has since been cited more than 1000 times. He highlighted numerous examples of research topics he viewed as having questionable merit. Studies have since accumulated for these associations. We systematically evaluated current evidence of 53 example associations discussed in the article. Approximately one-quarter of those presented as doubtful are now widely viewed as causal based on current evaluations of the public health consensus. They include associations between alcohol consumption and breast cancer, residential radon exposure and lung cancer, and the use of tanning devices and melanoma. This history should inform current debates about the reproducibility of epidemiologic research results.

5.
Sci Rep ; 10(1): 18051, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-33093519

RESUMO

Atrioventricular septal defects (AVSD) are a severe congenital heart defect present in individuals with Down syndrome (DS) at a > 2000-fold increased prevalence compared to the general population. This study aimed to identify risk-associated genes and pathways and to examine a potential polygenic contribution to AVSD in DS. We analyzed a total cohort of 702 individuals with DS with or without AVSD, with genomic data from whole exome sequencing, whole genome sequencing, and/or array-based imputation. We utilized sequence kernel association testing and polygenic risk score (PRS) methods to examine rare and common variants. Our findings suggest that the Notch pathway, particularly NOTCH4, as well as genes involved in the ciliome including CEP290 may play a role in AVSD in DS. These pathways have also been implicated in DS-associated AVSD in prior studies. A polygenic component for AVSD in DS has not been examined previously. Using weights based on the largest genome-wide association study of congenital heart defects available (2594 cases and 5159 controls; all general population samples), we found PRS to be associated with AVSD with odds ratios ranging from 1.2 to 1.3 per standard deviation increase in PRS and corresponding liability r2 values of approximately 1%, suggesting at least a small polygenic contribution to DS-associated AVSD. Future studies with larger sample sizes will improve identification and quantification of genetic contributions to AVSD in DS.


Assuntos
Antígenos de Neoplasias , Proteínas de Ciclo Celular , Proteínas do Citoesqueleto , Síndrome de Down/genética , Estudo de Associação Genômica Ampla , Defeitos dos Septos Cardíacos/genética , Receptor Notch4 , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Risco , Sequenciamento Completo do Genoma
6.
Sci Rep ; 9(1): 7523, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101869

RESUMO

Genetic studies of psychiatric disorders often deal with phenotypes that are not directly measurable. Instead, researchers rely on multivariate symptom data from questionnaires and surveys like the PTSD Symptom Scale (PSS) and Beck Depression Inventory (BDI) to indirectly assess a latent phenotype of interest. Researchers subsequently collapse such multivariate questionnaire data into a univariate outcome to represent a surrogate for the latent phenotype. However, when a causal variant is only associated with a subset of collapsed symptoms, the effect will be challenging to detect using the univariate outcome. We describe a more powerful strategy for genetic association testing in this situation that jointly analyzes the original multivariate symptom data collectively using a statistical framework that compares similarity in multivariate symptom-scale data from questionnaires to similarity in common genetic variants across a gene. We use simulated data to demonstrate this strategy provides substantially increased power over standard approaches that collapse questionnaire data into a single surrogate outcome. We also illustrate our approach using GWAS data from the Grady Trauma Project and identify genes associated with BDI not identified using standard univariate techniques. The approach is computationally efficient, scales to genome-wide studies, and is applicable to correlated symptom data of arbitrary dimension.


Assuntos
Estudos de Associação Genética/métodos , Transtornos Mentais/genética , Simulação por Computador , Depressão/genética , Estudos de Associação Genética/estatística & dados numéricos , Predisposição Genética para Doença , Humanos , Modelos Genéticos , Modelos Estatísticos , Análise Multivariada , Fenótipo , Polimorfismo de Nucleotídeo Único , Transtornos de Estresse Pós-Traumáticos/genética , Inquéritos e Questionários
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA