Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 299
Filtrar
1.
Nat Ecol Evol ; 3(11): 1598-1606, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31591491

RESUMO

Sequencing DNA derived from archaic bones has enabled genetic comparison of Neanderthals and anatomically modern humans (AMHs), and revealed that they interbred. However, interpreting what genetic differences imply about their phenotypic differences remains challenging. Here, we introduce an approach for identifying divergent gene regulation between archaic hominins, such as Neanderthals, and AMH sequences, and find 766 genes that are likely to have been divergently regulated (DR) by Neanderthal haplotypes that do not remain in AMHs. DR genes include many involved in phenotypes known to differ between Neanderthals and AMHs, such as the structure of the rib cage and supraorbital ridge development. They are also enriched for genes associated with spontaneous abortion, polycystic ovary syndrome, myocardial infarction and melanoma. Phenotypes associated with modern human variation in these genes' regulation in ~23,000 biobank patients further support their involvement in immune and cardiovascular phenotypes. Comparing DR genes between two Neanderthals and a Denisovan revealed divergence in the immune system and in genes associated with skeletal and dental morphology that are consistent with the archaeological record. These results establish differences in gene regulatory architecture between AMHs and archaic hominins, and provide an avenue for exploring phenotypic differences between archaic groups from genomic information alone.

2.
Brain ; 142(9): 2581-2589, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31497858

RESUMO

Autopsy measures of Alzheimer's disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer's disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer's disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer's disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 × 10-8) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 × 10-8) but not females (P = 0.85, sex-interaction P = 2.9 × 10-4). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.

4.
Nat Genet ; 51(6): 933-940, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31086352

RESUMO

The genetic architecture of psychiatric disorders is characterized by a large number of small-effect variants1 located primarily in non-coding regions, suggesting that the underlying causal effects may influence disease risk by modulating gene expression2-4. We provide comprehensive analyses using transcriptome data from an unprecedented collection of tissues to gain pathophysiological insights into the role of the brain, neuroendocrine factors (adrenal gland) and gastrointestinal systems (colon) in psychiatric disorders. In each tissue, we perform PrediXcan analysis and identify trait-associated genes for schizophrenia (n associations = 499; n unique genes = 275), bipolar disorder (n associations = 17; n unique genes = 13), attention deficit hyperactivity disorder (n associations = 19; n unique genes = 12) and broad depression (n associations = 41; n unique genes = 31). Importantly, both PrediXcan and summary-data-based Mendelian randomization/heterogeneity in dependent instruments analyses suggest potentially causal genes in non-brain tissues, showing the utility of these tissues for mapping psychiatric disease genetic predisposition. Our analyses further highlight the importance of joint tissue approaches as 76% of the genes were detected only in difficult-to-acquire tissues.


Assuntos
Perfilação da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Transtornos Mentais/genética , Transtornos Mentais/psicologia , Transcriptoma , Algoritmos , Biologia Computacional/métodos , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Estudos de Associação Genética/métodos , Estudo de Associação Genômica Ampla , Humanos , Transtornos Mentais/diagnóstico , Especificidade de Órgãos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Característica Quantitativa Herdável
5.
Nat Neurosci ; 22(5): 691-699, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30988527

RESUMO

Genome-wide association studies (GWAS) have identified more than 100 schizophrenia (SCZ)-associated loci, but using these findings to illuminate disease biology remains a challenge. Here we present integrative risk gene selector (iRIGS), a Bayesian framework that integrates multi-omics data and gene networks to infer risk genes in GWAS loci. By applying iRIGS to SCZ GWAS data, we predicted a set of high-confidence risk genes, most of which are not the nearest genes to the GWAS index variants. High-confidence risk genes account for a significantly enriched heritability, as estimated by stratified linkage disequilibrium score regression. Moreover, high-confidence risk genes are predominantly expressed in brain tissues, especially prenatally, and are enriched for targets of approved drugs, suggesting opportunities to reposition existing drugs for SCZ. Thus, iRIGS can leverage accumulating functional genomics and GWAS data to advance our understanding of SCZ etiology and potential therapeutics.


Assuntos
Redes Reguladoras de Genes , Predisposição Genética para Doença , Genômica/métodos , Esquizofrenia/genética , Animais , Teorema de Bayes , Modelos Animais de Doenças , Estudo de Associação Genômica Ampla , Humanos , Camundongos , Fatores de Risco
6.
Clin Cancer Res ; 25(13): 4104-4116, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30952644

RESUMO

PURPOSE: Cisplatin, a commonly used chemotherapeutic, results in tinnitus, the phantom perception of sound. Our purpose was to identify the clinical and genetic determinants of tinnitus among testicular cancer survivors (TCS) following cisplatin-based chemotherapy. EXPERIMENTAL DESIGN: TCS (n = 762) were dichotomized to cases (moderate/severe tinnitus; n = 154) and controls (none; n = 608). Logistic regression was used to evaluate associations with comorbidities and SNP dosages in genome-wide association study (GWAS) following quality control and imputation (covariates: age, noise exposure, cisplatin dose, genetic principal components). Pathway over-representation tests and functional studies in mouse auditory cells were performed. RESULTS: Cisplatin-induced tinnitus (CisIT) significantly associated with age at diagnosis (P = 0.007) and cumulative cisplatin dose (P = 0.007). CisIT prevalence was not significantly greater in 400 mg/m2-treated TCS compared with 300 (P = 0.41), but doses >400 mg/m2 (median 580, range 402-828) increased risk by 2.61-fold (P < 0.0001). CisIT cases had worse hearing at each frequency (0.25-12 kHz, P < 0.0001), and reported more vertigo (OR = 6.47; P < 0.0001) and problems hearing in a crowd (OR = 8.22; P < 0.0001) than controls. Cases reported poorer health (P < 0.0001) and greater psychotropic medication use (OR = 2.4; P = 0.003). GWAS suggested a variant near OTOS (rs7606353, P = 2 × 10-6) and OTOS eQTLs were significantly enriched independently of that SNP (P = 0.018). OTOS overexpression in HEI-OC1, a mouse auditory cell line, resulted in resistance to cisplatin-induced cytotoxicity. Pathway analysis implicated potassium ion transport (q = 0.007). CONCLUSIONS: CisIT associated with several neuro-otological symptoms, increased use of psychotropic medication, and poorer health. OTOS, expressed in the cochlear lateral wall, was implicated as protective. Future studies should investigate otoprotective targets in supporting cochlear cells.

7.
N Engl J Med ; 380(15): 1478-1479, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30970195
8.
Am J Hum Genet ; 104(3): 503-519, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30827500

RESUMO

Although the use of model systems for studying the mechanism of mutations that have a large effect is common, we highlight here the ways that zebrafish-model-system studies of a gene, GRIK5, that contributes to the polygenic liability to develop eye diseases have helped to illuminate a mechanism that implicates vascular biology in eye disease. A gene-expression prediction derived from a reference transcriptome panel applied to BioVU, a large electronic health record (EHR)-linked biobank at Vanderbilt University Medical Center, implicated reduced GRIK5 expression in diverse eye diseases. We tested the function of GRIK5 by depletion of its ortholog in zebrafish, and we observed reduced blood vessel numbers and integrity in the eye and increased vascular permeability. Analyses of EHRs in >2.6 million Vanderbilt subjects revealed significant comorbidity of eye and vascular diseases (relative risks 2-15); this comorbidity was confirmed in 150 million individuals from a large insurance claims dataset. Subsequent studies in >60,000 genotyped BioVU participants confirmed the association of reduced genetically predicted expression of GRIK5 with comorbid vascular and eye diseases. Our studies pioneer an approach that allows a rapid iteration of the discovery of gene-phenotype relationships to the primary genetic mechanism contributing to the pathophysiology of human disease. Our findings also add dimension to the understanding of the biology driven by glutamate receptors such as GRIK5 (also referred to as GLUK5 in protein form) and to mechanisms contributing to human eye diseases.

9.
Nat Genet ; 51(4): 659-674, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30911161

RESUMO

Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.


Assuntos
Encéfalo/fisiopatologia , Expressão Gênica/genética , Esquizofrenia/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Risco , Transcriptoma/genética
10.
J Neurotrauma ; 36(14): 2167-2177, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30773988

RESUMO

Post-concussion syndrome (PCS) is characterized by persistent cognitive, somatic, and emotional symptoms after a mild traumatic brain injury (mTBI). Genetic and other biological variables may contribute to PCS etiology, and the emergence of biobanks linked to electronic health records (EHRs) offers new opportunities for research on PCS. We sought to validate the EHR data of PCS patients by comparing two diagnostic algorithms deployed in the Vanderbilt University Medical Center de-identified database of 2.8 million patient EHRs. The algorithms identified individuals with PCS by: 1) natural language processing (NLP) of narrative text in the EHR combined with structured demographic, diagnostic, and encounter data; or 2) coded billing and procedure data. The predictive value of each algorithm was assessed, and cases and controls identified by each approach were compared on demographic and medical characteristics. The NLP algorithm identified 507 cases and 10,857 controls. The negative predictive value in controls was 78% and the positive predictive value (PPV) in cases was 82%. Conversely, the coded algorithm identified 1142 patients with two or more PCS billing codes and had a PPV of 76%. Comparisons of PCS controls to both case groups recovered known epidemiology of PCS: cases were more likely than controls to be female and to have pre-morbid diagnoses of anxiety, migraine, and post-traumatic stress disorder. In contrast, controls and cases were equally likely to have attention deficit hyperactive disorder and learning disabilities, in accordance with the findings of recent systematic reviews of PCS risk factors. We conclude that EHRs are a valuable research tool for PCS. Ascertainment based on coded data alone had a predictive value comparable to an NLP algorithm, recovered known PCS risk factors, and maximized the number of included patients.

11.
JCI Insight ; 3(20)2018 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-30333305

RESUMO

Aortic dissection (AD) is a life-threatening vascular disease with limited treatment strategies. Here, we show that loss of the GWAS-identified SH2B3 gene, encoding lymphocyte adaptor protein LNK, markedly increases susceptibility to acute AD and rupture in response to angiotensin (Ang) II infusion. As early as day 3 following Ang II infusion, prior to the development of AD, Lnk-/- aortas display altered mechanical properties, increased elastin breaks, collagen thinning, enhanced neutrophil accumulation, and increased MMP-9 activity compared with WT mice. Adoptive transfer of Lnk-/- leukocytes into Rag1-/- mice induces AD and rupture in response to Ang II, demonstrating that LNK deficiency in hematopoietic cells plays a key role in this disease. Interestingly, treatment with doxycycline prevents the early accumulation of aortic neutrophils and significantly reduces the incidence of AD and rupture. PrediXcan analysis in a biobank of more than 23,000 individuals reveals that decreased expression of SH2B3 is significantly associated with increased frequency of AD-related phenotypes (odds ratio 0.81). Thus, we identified a role for LNK in the pathology of AD in experimental animals and humans and describe a new model that can be used to inform both inherited and acquired forms of this disease.

12.
Bioinformatics ; 2018 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-30256891

RESUMO

Motivation: Given the complexity of genome regions, prioritize the functional effects of noncoding variants remains a challenge. Although several frameworks have been proposed for the evaluation of the functionality of noncoding variants, most of them used "black boxes" methods that simplify the task as the pathogenicity/benign classification problem, which ignores the distinct regulatory mechanisms of variants and leads to less desirable performance. In this study, we developed DVAR, an unsupervised framework that leverage various biochemical and evolutionary evidence to distinguish the gene regulatory categories of variants and assess their comprehensive functional impact simultaneously. Results: DVAR performed de novo pattern discovery in high-dimensional data and identified five regulatory clusters of noncoding variants. Leveraging the new insights into the multiple functional patterns, it measures both the between-class and the within-class functional implication of the variants to achieve accurate prioritization. Compared to other two-class learning methods, it showed improved performance in identification of clinically significant variants, fine-mapped GWAS variants, eQTLs and expression-modulating variants. Moreover, it has superior performance on disease causal variants verified by genome editing (like CRISPR-Cas9), which could provide a pre-selection strategy for genome editing technologies across the whole genome. Finally, evaluated in BioVU and UK Biobank, two large-scale DNA biobanks linked to complete electronic health records (EHR), DVAR demonstrated its effectiveness in prioritizing noncoding variants associated with medical phenotypes. Availability: The C++ and Python source codes, the pre-computed DVAR-cluster labels and DVAR scores across the whole genome are available at https://www.vumc.org/cgg/dvar. Supplementary information: Supplementary data are available at Bioinformatics online.

13.
PLoS Med ; 15(8): e1002642, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30153257

RESUMO

BACKGROUND: Observations from statin clinical trials and from Mendelian randomization studies suggest that low low-density lipoprotein cholesterol (LDL-C) concentrations may be associated with increased risk of type 2 diabetes mellitus (T2DM). Despite the findings from statin clinical trials and genetic studies, there is little direct evidence implicating low LDL-C concentrations in increased risk of T2DM. METHODS AND FINDINGS: We used de-identified electronic health records (EHRs) at Vanderbilt University Medical Center to compare the risk of T2DM in a cross-sectional study among individuals with very low (≤60 mg/dl, N = 8,943) and normal (90-130 mg/dl, N = 71,343) LDL-C levels calculated using the Friedewald formula. LDL-C levels associated with statin use, hospitalization, or a serum albumin level < 3 g/dl were excluded. We used a 2-phase approach: in 1/3 of the sample (discovery) we used T2DM phenome-wide association study codes (phecodes) to identify cases and controls, and in the remaining 2/3 (validation) we identified T2DM cases and controls using a validated algorithm. The analysis plan for the validation phase was constructed at the time of the design of that component of the study. The prevalence of T2DM in the very low and normal LDL-C groups was compared using logistic regression with adjustment for age, race, sex, body mass index (BMI), high-density lipoprotein cholesterol, triglycerides, and duration of care. Secondary analyses included prespecified stratification by sex, race, BMI, and LDL-C level. In the discovery cohort, phecodes related to T2DM were significantly more frequent in the very low LDL-C group. In the validation cohort (N = 33,039 after applying the T2DM algorithm to identify cases and controls), the risk of T2DM was increased in the very low compared to normal LDL-C group (odds ratio [OR] 2.06, 95% CI 1.80-2.37; P < 2 × 10-16). The findings remained significant in sensitivity analyses. The association between low LDL-C levels and T2DM was significant in males (OR 2.43, 95% CI 2.00-2.95; P < 2 × 10-16) and females (OR 1.74, 95% CI 1.42-2.12; P = 6.88 × 10-8); in normal weight (OR 2.18, 95% CI 1.59-2.98; P = 1.1× 10-6), overweight (OR 2.17, 95% CI 1.65-2.83; P = 1.73× 10-8), and obese (OR 2.00, 95% CI 1.65-2.41; P = 8 × 10-13) categories; and in individuals with LDL-C < 40 mg/dl (OR 2.31, 95% CI 1.71-3.10; P = 3.01× 10-8) and LDL-C 40-60 mg/dl (OR 1.99, 95% CI 1.71-2.32; P < 2.0× 10-16). The association was significant in individuals of European ancestry (OR 2.67, 95% CI 2.25-3.17; P < 2 × 10-16) but not in those of African ancestry (OR 1.09, 95% CI 0.81-1.46; P = 0.56). A limitation was that we only compared groups with very low and normal LDL-C levels; also, since this was not an inception cohort, we cannot exclude the possibility of reverse causation. CONCLUSIONS: Very low LDL-C concentrations occurring in the absence of statin treatment were significantly associated with T2DM risk in a large EHR population; this increased risk was present in both sexes and all BMI categories, and in individuals of European ancestry but not of African ancestry. Longitudinal cohort studies to assess the relationship between very low LDL-C levels not associated with lipid-lowering therapy and risk of developing T2DM will be important.

14.
Acta Neuropathol ; 136(6): 857-872, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29967939

RESUMO

Cerebrospinal fluid (CSF) levels of amyloid-ß 42 (Aß42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aß42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aß42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (ß = - 0.03, p = 4.25 × 10-8; ß = 0.03, p = 3.97 × 10-8) than males (ß = - 0.02, p = 0.009; ß = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (ß = 0.05, p = 4.57 × 10-10) compared to males (ß = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.

15.
Emerg Infect Dis ; 24(7): 1178-1187, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29916350

RESUMO

The need for closer linkages between scientific and programmatic areas focused on addressing vaccine-preventable and acute respiratory infections led to establishment of the National Center for Immunization and Respiratory Diseases (NCIRD) at the Centers for Disease Control and Prevention. During its first 10 years (2006-2015), NCIRD worked with partners to improve preparedness and response to pandemic influenza and other emergent respiratory infections, provide an evidence base for addition of 7 newly recommended vaccines, and modernize vaccine distribution. Clinical tools were developed for improved conversations with parents, which helped sustain childhood immunization as a social norm. Coverage increased for vaccines to protect adolescents against pertussis, meningococcal meningitis, and human papillomavirus-associated cancers. NCIRD programs supported outbreak response for new respiratory pathogens and oversaw response of the Centers for Disease Control and Prevention to the 2009 influenza A(H1N1) pandemic. Other national public health institutes might also find closer linkages between epidemiology, laboratory, and immunization programs useful.

16.
Nat Genet ; 50(7): 956-967, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29955180

RESUMO

We apply integrative approaches to expression quantitative loci (eQTLs) from 44 tissues from the Genotype-Tissue Expression project and genome-wide association study data. About 60% of known trait-associated loci are in linkage disequilibrium with a cis-eQTL, over half of which were not found in previous large-scale whole blood studies. Applying polygenic analyses to metabolic, cardiovascular, anthropometric, autoimmune, and neurodegenerative traits, we find that eQTLs are significantly enriched for trait associations in relevant pathogenic tissues and explain a substantial proportion of the heritability (40-80%). For most traits, tissue-shared eQTLs underlie a greater proportion of trait associations, although tissue-specific eQTLs have a greater contribution to some traits, such as blood pressure. By integrating information from biological pathways with eQTL target genes and applying a gene-based approach, we validate previously implicated causal genes and pathways, and propose new variant and gene associations for several complex traits, which we replicate in the UK BioBank and BioVU.

17.
Artigo em Inglês | MEDLINE | ID: mdl-29727518

RESUMO

The 1918 devastating influenza pandemic left a lasting impact on influenza experts and the public, and the importance of global influenza surveillance was soon recognized. The World Health Organization (WHO) Global Influenza Surveillance Network (GISN) was founded in 1952 and renamed to Global Influenza Surveillance and Response System in 2011 upon the adoption by the World Health Assembly, of the Pandemic Influenza Preparedness Framework for the Sharing of Influenza Viruses and Access to Vaccines and Other Benefits ("PIP Framework"). The importance of influenza surveillance had been recognized and promoted by experts prior to the years leading up to the establishment of WHO. In the 65 years of its existence, the Network has grown to comprise 143 National Influenza Centers recognized by WHO, 6 WHO Collaborating Centers, 4 Essential Regulatory Laboratories, and 13 H5 Reference Laboratories. The Network has proven its excellence throughout these 65 years, providing detailed information on circulating seasonal influenza viruses, as well as immediate response to the influenza pandemics in 1957, 1968, and 2009, and to threats caused by animal influenza viruses and by zoonotic transmission of coronaviruses. For its central role in global public health, the Network has been highly recognized by its many partners and by international bodies. Several generations of world-renowned influenza scientists have brought the Network to where it is now and they will take it forward to the future, as influenza will remain a preeminent threat to humans and to animals.

18.
Nat Commun ; 9(1): 1825, 2018 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-29739930

RESUMO

Scalable, integrative methods to understand mechanisms that link genetic variants with phenotypes are needed. Here we derive a mathematical expression to compute PrediXcan (a gene mapping approach) results using summary data (S-PrediXcan) and show its accuracy and general robustness to misspecified reference sets. We apply this framework to 44 GTEx tissues and 100+ phenotypes from GWAS and meta-analysis studies, creating a growing public catalog of associations that seeks to capture the effects of gene expression variation on human phenotypes. Replication in an independent cohort is shown. Most of the associations are tissue specific, suggesting context specificity of the trait etiology. Colocalized significant associations in unexpected tissues underscore the need for an agnostic scanning of multiple contexts to improve our ability to detect causal regulatory mechanisms. Monogenic disease genes are enriched among significant associations for related traits, suggesting that smaller alterations of these genes may cause a spectrum of milder phenotypes.

19.
20.
Circulation ; 138(17): 1839-1849, 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-29703846

RESUMO

BACKGROUND: Coronary heart disease (CHD) is a leading cause of death globally. Although therapy with statins decreases circulating levels of low-density lipoprotein cholesterol and the incidence of CHD, additional events occur despite statin therapy in some individuals. The genetic determinants of this residual cardiovascular risk remain unknown. METHODS: We performed a 2-stage genome-wide association study of CHD events during statin therapy. We first identified 3099 cases who experienced CHD events (defined as acute myocardial infarction or the need for coronary revascularization) during statin therapy and 7681 controls without CHD events during comparable intensity and duration of statin therapy from 4 sites in the Electronic Medical Records and Genomics Network. We then sought replication of candidate variants in another 160 cases and 1112 controls from a fifth Electronic Medical Records and Genomics site, which joined the network after the initial genome-wide association study. Finally, we performed a phenome-wide association study for other traits linked to the most significant locus. RESULTS: The meta-analysis identified 7 single nucleotide polymorphisms at a genome-wide level of significance within the LPA/PLG locus associated with CHD events on statin treatment. The most significant association was for an intronic single nucleotide polymorphism within LPA/PLG (rs10455872; minor allele frequency, 0.069; odds ratio, 1.58; 95% confidence interval, 1.35-1.86; P=2.6×10-10). In the replication cohort, rs10455872 was also associated with CHD events (odds ratio, 1.71; 95% confidence interval, 1.14-2.57; P=0.009). The association of this single nucleotide polymorphism with CHD events was independent of statin-induced change in low-density lipoprotein cholesterol (odds ratio, 1.62; 95% confidence interval, 1.17-2.24; P=0.004) and persisted in individuals with low-density lipoprotein cholesterol ≤70 mg/dL (odds ratio, 2.43; 95% confidence interval, 1.18-4.75; P=0.015). A phenome-wide association study supported the effect of this region on coronary heart disease and did not identify noncardiovascular phenotypes. CONCLUSIONS: Genetic variations at the LPA locus are associated with CHD events during statin therapy independently of the extent of low-density lipoprotein cholesterol lowering. This finding provides support for exploring strategies targeting circulating concentrations of lipoprotein(a) to reduce CHD events in patients receiving statins.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA