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1.
Aging (Albany NY) ; 132021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846280

RESUMO

Alzheimer's disease (AD) is the most common form of dementia, currently affecting 35 million people worldwide. Apolipoprotein E (APOE) ε4 allele is the major risk factor for sporadic, late-onset AD (LOAD), which comprises over 95% of AD cases, increasing the risk of AD 4-12 fold. Despite this, the role of APOE in AD pathogenesis is still a mystery. Aiming for a better understanding of APOE-specific effects, the ADAPTED consortium analysed and integrated publicly available data of multiple OMICS technologies from both plasma and brain stratified by APOE haplotype (APOE2, APOE3 and APOE4). Combining genome-wide association studies (GWAS) with differential mRNA and protein expression analyses and single-nuclei transcriptomics, we identified genes and pathways contributing to AD in both APOE dependent and independent fashion. Interestingly, we characterised a set of biomarkers showing plasma and brain consistent protein profiles and opposite trends in APOE2 and APOE4 AD cases that could constitute screening tools for a disease that lacks specific blood biomarkers. Beside the identification of APOE-specific signatures, our findings advocate that this novel approach, based on the concordance across OMIC layers and tissues, is an effective strategy for overcoming the limitations of often underpowered single-OMICS studies.

2.
Nat Commun ; 11(1): 6285, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33293549

RESUMO

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.

3.
Nat Commun ; 11(1): 4796, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963231

RESUMO

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/ß-catenin, TGF-ß and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.


Assuntos
Envelhecimento/genética , Encéfalo , Estudo de Associação Genômica Ampla , Transtornos Mentais/genética , Doenças Neurodegenerativas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estruturas Cromossômicas , Cognição , Feminino , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único
4.
Transl Psychiatry ; 10(1): 245, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32699239

RESUMO

Cognitive function such as reasoning, attention, memory, and language is strongly correlated with brain aging. Compared to non-Hispanic whites, Hispanics/Latinos have a higher risk of cognitive impairment and dementia. The genetic determinants of cognitive function have not been widely explored in this diverse and admixed population. We conducted a genome-wide association analysis of cognitive function in up to 7600 middle aged and older Hispanics/Latinos (mean = 55 years) from the Hispanic Community Health Study / Study of Latinos (HCHS/SOL). Four cognitive measures were examined: the Brief Spanish English Verbal Learning Test (B-SEVLT), the Word Fluency Test (WFT), the Digit Symbol Substitution Test (DSST), the Six-Item Screener (SIS). Four novel loci were identified: one for B-SEVLT at 4p14, two for WFT at 3p14.1 and 6p21.32, and one for DSST at 10p13. These loci implicate genes highly expressed in brain and previously connected to neurological diseases (UBE2K, FRMD4B, the HLA gene complex). By applying tissue-specific gene expression prediction models to our genotype data, additional genes highly expressed in brain showed suggestive associations with cognitive measures possibly indicating novel biological mechanisms, including IFT122 in the hippocampus for SIS, SNX31 in the basal ganglia for B-SEVLT, RPS6KB2 in the frontal cortex for WFT, and CSPG5 in the hypothalamus for DSST. These findings provide new information about the genetic determinants of cognitive function in this unique population. In addition, we derived a measure of general cognitive function based on these cognitive tests and generated genome-wide association summary results, providing a resource to the research community for comparison, replication, and meta-analysis in future genetic studies in Hispanics/Latinos.

5.
Cereb Cortex ; 30(7): 4121-4139, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32198502

RESUMO

We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade-albeit in a very limited manner-to behaviors as complex as the choice of one's occupation.

7.
Mol Psychiatry ; 25(8): 1859-1875, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-30108311

RESUMO

The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10-7), an immunoglobulin gene whose antibodies interact with ß-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10-7), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10-6). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

8.
Nat Genet ; 51(11): 1624-1636, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31636452

RESUMO

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.


Assuntos
Encéfalo/anatomia & histologia , Encéfalo/metabolismo , Drosophila melanogaster/metabolismo , Variação Genética , Estudo de Associação Genômica Ampla , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Adulto , Idoso , Animais , Estudos de Coortes , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Tamanho do Órgão
10.
Nat Genet ; 51(3): 414-430, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30820047

RESUMO

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aß processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Imunidade/genética , Lipídeos/genética , Proteínas tau/genética , Idoso , Estudos de Casos e Controles , Feminino , Testes Genéticos/métodos , Estudo de Associação Genômica Ampla/métodos , Haplótipos/genética , Humanos , Metabolismo dos Lipídeos/genética , Masculino
11.
Brain ; 142(4): 1009-1023, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30859180

RESUMO

We report a composite extreme phenotype design using distribution of white matter hyperintensities and brain infarcts in a population-based cohort of older persons for gene-mapping of cerebral small vessel disease. We demonstrate its application in the 3C-Dijon whole exome sequencing (WES) study (n = 1924, nWESextremes = 512), with both single variant and gene-based association tests. We used other population-based cohort studies participating in the CHARGE consortium for replication, using whole exome sequencing (nWES = 2,868, nWESextremes = 956) and genome-wide genotypes (nGW = 9924, nGWextremes = 3308). We restricted our study to candidate genes known to harbour mutations for Mendelian small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2 and TREX1. We identified significant associations of a common intronic variant in HTRA1, rs2293871 using single variant association testing (Pdiscovery = 8.21 × 10-5, Preplication = 5.25 × 10-3, Pcombined = 4.72 × 10-5) and of NOTCH3 using gene-based tests (Pdiscovery = 1.61 × 10-2, Preplication = 3.99 × 10-2, Pcombined = 5.31 × 10-3). Follow-up analysis identified significant association of rs2293871 with small vessel ischaemic stroke, and two blood expression quantitative trait loci of HTRA1 in linkage disequilibrium. Additionally, we identified two participants in the 3C-Dijon cohort (0.4%) carrying heterozygote genotypes at known pathogenic variants for familial small vessel disease within NOTCH3 and HTRA1. In conclusion, our proof-of-concept study provides strong evidence that using a novel composite MRI-derived phenotype for extremes of small vessel disease can facilitate the identification of genetic variants underlying small vessel disease, both common variants and those with rare and low frequency. The findings demonstrate shared mechanisms and a continuum between genes underlying Mendelian small vessel disease and those contributing to the common, multifactorial form of the disease.


Assuntos
Doenças de Pequenos Vasos Cerebrais/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Receptor Notch3/genética , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/genética , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/metabolismo , Estudos de Coortes , Feminino , Heterozigoto , Serina Peptidase 1 de Requerimento de Alta Temperatura A/metabolismo , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Receptor Notch3/metabolismo , Receptor Notch3/fisiologia , Acidente Vascular Cerebral/genética , Substância Branca/diagnóstico por imagem , Substância Branca/metabolismo , Sequenciamento Completo do Exoma/métodos
12.
Neurology ; 92(16): e1890-e1898, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30867269

RESUMO

OBJECTIVE: To identify promising blood-based biomarkers and novel etiologic pathways of disease risk, we applied an untargeted serum metabolomics profiling in a community-based prospective study of ischemic stroke (IS). METHODS: In 3,904 men and women from the Atherosclerosis Risk In Communities study, Cox proportional hazard models were used to estimate the association of incident IS with the standardized level of 245 fasting serum metabolites individually, adjusting for age, sex, race, field center, batch, diabetes, hypertension, current smoking status, body mass index, and estimated glomerular filtration rate. Validation of results was carried out in an independent sample of 114 IS cases and 112 healthy controls. RESULTS: Serum levels of 2 long-chain dicarboxylic acids, tetradecanedioate and hexadecanedioate, were strongly correlated (r = 0.88) and were associated with incident IS after adjusting for covariates (hazard ratio [95% confidence interval (CI)] 1.11 [1.06-1.16] and 1.12 [1.07-1.17], respectively; p < 0.0001). Analyses by IS subtypes suggested that these associations were specific to cardioembolic stroke (CES). Associations of tetradecanedioate and hexadecanedioate with IS were independently confirmed (odds ratio [95% CI] 1.76 [1.21; 2.56] and 1.60 [1.11; 2.32], respectively). CONCLUSION: Two serum long-chain dicarboxylic acids, metabolic products of ω-oxidation of fatty acids, were associated with IS and CES independently of known risk factors. Pathways related to intracellular hexadecanedioate synthesis or those involved in its clearance from the circulation may mediate IS risk. These results highlight the potential of metabolomics to discover novel circulating biomarkers for stroke and to unravel novel pathways for IS and its subtypes.


Assuntos
Isquemia Encefálica/sangue , Acidente Vascular Cerebral/sangue , Biomarcadores/sangue , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/genética , Feminino , Seguimentos , Estudos de Associação Genética , Humanos , Incidência , Masculino , Metaboloma , Metabolômica , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/genética
13.
Neurology ; 2019 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-30651383

RESUMO

OBJECTIVE: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. METHODS: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. RESULTS: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p [BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p [BI] = 4.4 × 10-10; p [SSBI] = 1.2 × 10-4), diabetes (p [BI] = 1.7 × 10-8; p [SSBI] = 2.8 × 10-3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10-24), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. CONCLUSION: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.

14.
Sci Rep ; 8(1): 17578, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30546063

RESUMO

The apoE4 isoform is associated with increased cholesterol, cardiovascular risk, and Alzheimer's Disease risk, however, its distribution is not well-understood among US Latinos. Latinos living in the US are highly Amerindian, European and African admixed, which varies by region and country of origin. However, Latino genetic diversity is understudied and consequently poorly understood, which has significant implications for understanding disease risk in nearly one-fifth of the US population. In this report we describe apoE distributions in a large and representative sample of diverse, genetically determined US Latinos.


Assuntos
Doença de Alzheimer/genética , Apolipoproteínas E/genética , Doenças Cardiovasculares/genética , Variação Genética , Genótipo , Hispano-Americanos/genética , Adulto , Idoso , Doença de Alzheimer/sangue , Apolipoproteínas E/sangue , Doenças Cardiovasculares/sangue , Colesterol/sangue , Colesterol/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Estados Unidos
15.
Nat Commun ; 9(1): 3945, 2018 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-30258056

RESUMO

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρgenetic = -0.59, p-value = 3.14 × 10-6), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.


Assuntos
Genoma Humano , Ventrículos Laterais/anatomia & histologia , Idoso , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Tamanho do Órgão/genética
16.
Stroke ; 49(8): 1812-1819, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30002152

RESUMO

Background and Purpose- White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods- In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results- At 17q25, we confirmed the association of multiple common variants in TRIM65, FBF1, and ACOX1 ( P<6×10-7). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; PEA=4.5×10-8) partially independent of known common signal ( PEA(conditional)=1.4×10-3). We further identified a locus at 2q33 containing common variants in NBEAL1, CARF, and WDR12 (lead, rs2351524; Pall=1.9×10-10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants ( Prs34136221=2.8×10-8). Conclusions- Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.


Assuntos
Encéfalo/diagnóstico por imagem , Exoma/genética , Variação Genética/genética , Imagem por Ressonância Magnética/métodos , Proteínas Mitocondriais/genética , Substância Branca/diagnóstico por imagem , Estudos de Coortes , Humanos
18.
Bioinformatics ; 34(16): 2724-2731, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29590295

RESUMO

Motivation: Annotation of genomic variants is an increasingly important and complex part of the analysis of sequence-based genomic analyses. Computational predictions of variant function are routinely incorporated into gene-based analyses of rare-variants, though to date most studies use limited information for assessing variant function that is often agnostic of the disease being studied. Results: In this work, we outline an annotation process motivated by the Alzheimer's Disease Sequencing Project, illustrate the impact of including tissue-specific transcript sets and sources of gene regulatory information and assess the potential impact of changing genomic builds on the annotation process. While these factors only impact a small proportion of total variant annotations (∼5%), they influence the potential analysis of a large fraction of genes (∼25%). Availability and implementation: Individual variant annotations are available via the NIAGADS GenomicsDB, at https://www.niagads.org/genomics/ tools-and-software/databases/genomics-database. Annotations are also available for bulk download at https://www.niagads.org/datasets. Annotation processing software is available at http://www.icompbio.net/resources/software-and-downloads/. Supplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença , Anotação de Sequência Molecular/métodos , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos , Software , Bases de Dados Genéticas , Genoma , Genômica , Humanos
19.
Methods Mol Biol ; 1498: 191-197, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27709577

RESUMO

In silico prediction methods have increasingly been valuable and popular in molecular biology, especially in human genetics, for deleteriousness prediction to filter and prioritize huge amounts of DNA variation identified by sequencing human genomes. There is a rich collection of available methods developed upon different levels/aspects of knowledge about how DNA variations affect gene expression. Given the fact that their predictions are not always consistent or even opposite of what was expected, using consensus prediction or majority vote among these methods is preferred to trusting any single one. Because querying different databases for different methods is both tedious and time-consuming for such big data sets, one database integrating predictions from multiple databases can facilitate the process. In this chapter, we describe the general steps of obtaining comprehensive predictions and annotations for large numbers of variants from dbNSFP, the first and probably the most widely used database of its kind.


Assuntos
Genoma Humano/genética , Polimorfismo de Nucleotídeo Único/genética , Biologia Computacional/métodos , Simulação por Computador , Bases de Dados Genéticas , Expressão Gênica/genética , Humanos
20.
Hum Mol Genet ; 24(8): 2125-37, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25552646

RESUMO

Accurate deleteriousness prediction for nonsynonymous variants is crucial for distinguishing pathogenic mutations from background polymorphisms in whole exome sequencing (WES) studies. Although many deleteriousness prediction methods have been developed, their prediction results are sometimes inconsistent with each other and their relative merits are still unclear in practical applications. To address these issues, we comprehensively evaluated the predictive performance of 18 current deleteriousness-scoring methods, including 11 function prediction scores (PolyPhen-2, SIFT, MutationTaster, Mutation Assessor, FATHMM, LRT, PANTHER, PhD-SNP, SNAP, SNPs&GO and MutPred), 3 conservation scores (GERP++, SiPhy and PhyloP) and 4 ensemble scores (CADD, PON-P, KGGSeq and CONDEL). We found that FATHMM and KGGSeq had the highest discriminative power among independent scores and ensemble scores, respectively. Moreover, to ensure unbiased performance evaluation of these prediction scores, we manually collected three distinct testing datasets, on which no current prediction scores were tuned. In addition, we developed two new ensemble scores that integrate nine independent scores and allele frequency. Our scores achieved the highest discriminative power compared with all the deleteriousness prediction scores tested and showed low false-positive prediction rate for benign yet rare nonsynonymous variants, which demonstrated the value of combining information from multiple orthologous approaches. Finally, to facilitate variant prioritization in WES studies, we have pre-computed our ensemble scores for 87 347 044 possible variants in the whole-exome and made them publicly available through the ANNOVAR software and the dbNSFP database.


Assuntos
Biologia Computacional/métodos , Exoma , Polimorfismo de Nucleotídeo Único , Biologia Computacional/instrumentação , Genoma Humano , Humanos , Software
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