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1.
Nat Commun ; 11(1): 5404, 2020 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-33106479

RESUMO

There is a robust observational relationship between lower birthweight and higher risk of cardiometabolic disease in later life. The Developmental Origins of Health and Disease (DOHaD) hypothesis posits that adverse environmental factors in utero increase future risk of cardiometabolic disease. Here, we explore if a genetic risk score (GRS) of maternal SNPs associated with offspring birthweight is also associated with offspring cardiometabolic risk factors, after controlling for offspring GRS, in up to 26,057 mother-offspring pairs (and 19,792 father-offspring pairs) from the Nord-Trøndelag Health (HUNT) Study. We find little evidence for a maternal (or paternal) genetic effect of birthweight associated variants on offspring cardiometabolic risk factors after adjusting for offspring GRS. In contrast, offspring GRS is strongly related to many cardiometabolic risk factors, even after conditioning on maternal GRS. Our results suggest that the maternal intrauterine environment, as proxied by maternal SNPs that influence offspring birthweight, is unlikely to be a major determinant of adverse cardiometabolic outcomes in population based samples of individuals.


Assuntos
Peso ao Nascer , Doenças Cardiovasculares/genética , Herança Materna , Adulto , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Masculino , Análise da Randomização Mendeliana , Noruega/epidemiologia , Herança Paterna , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Adulto Jovem
2.
PLoS One ; 15(10): e0233941, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33108378

RESUMO

We aimed to estimate the rate of germline mutations in the offspring of individuals accidentally exposed to Cesium-137 ionizing radiation. The study included two distinct groups: one of cases, consisting of males and females accidentally exposed to low doses of ionizing radiation of Cs137, and a control group of non-exposed participants. The cases included 37 people representing 11 families and 15 children conceived after the accident. Exposed families incurred radiation absorbed doses in the range of 0.2 to 0.5 Gray. The control group included 15 families and 15 children also conceived after 1987 in Goiânia with no history of radiation exposure. DNA samples from peripheral blood were analyzed with the Affymetrix GeneChip® CytoScanHD™ to estimate point mutations in autosomal SNPs. A set of scripts previously developed was used to detect de novo mutations by comparing parent and offspring genotypes at the level of each SNP marker. Overall numbers of observed Mendelian deviations were statistically significant between the exposed and control groups. Our retrospective transgenerational DNA analysis showed a 44.0% increase in the burden of SNP mutations in the offspring of cases when compared to controls, based on the average of MFMD for the two groups. Parent-of-origin and type of nucleotide substitution were also inferred. This proved useful in a retrospective estimation of the rate of de novo germline mutations in a human population accidentally exposed to low doses of radiation from Cesium-137. Our results suggested that observed burden of germline mutations identified in offspring was a potentially useful biomarker of effect to estimate parental exposure to low doses of IR and could become an important marker suitable for biomonitoring human population exposed to environmental mutagens.


Assuntos
Radioisótopos de Césio/efeitos adversos , Técnicas de Genotipagem/métodos , Mutação em Linhagem Germinativa , Polimorfismo de Nucleotídeo Único , Exposição à Radiação/efeitos adversos , Adolescente , Adulto , Substituição de Aminoácidos , Estudos de Casos e Controles , Criança , Pré-Escolar , Desastres , Feminino , Humanos , Lactente , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Linhagem , Radiação Ionizante , Liberação Nociva de Radioativos , Estudos Retrospectivos , Adulto Jovem
4.
Nat Commun ; 11(1): 4930, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004804

RESUMO

Inference of causality between gene expression and complex traits using Mendelian randomization (MR) is confounded by pleiotropy and linkage disequilibrium (LD) of gene-expression quantitative trait loci (eQTL). Here, we propose an MR method, MR-link, that accounts for unobserved pleiotropy and LD by leveraging information from individual-level data, even when only one eQTL variant is present. In simulations, MR-link shows false-positive rates close to expectation (median 0.05) and high power (up to 0.89), outperforming all other tested MR methods and coloc. Application of MR-link to low-density lipoprotein cholesterol (LDL-C) measurements in 12,449 individuals with expression and protein QTL summary statistics from blood and liver identifies 25 genes causally linked to LDL-C. These include the known SORT1 and ApoE genes as well as PVRL2, located in the APOE locus, for which a causal role in liver was not known. Our results showcase the strength of MR-link for transcriptome-wide causal inferences.


Assuntos
LDL-Colesterol/sangue , Regulação da Expressão Gênica , Predisposição Genética para Doença , Modelos Genéticos , Locos de Características Quantitativas , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , LDL-Colesterol/metabolismo , Simulação por Computador , Conjuntos de Dados como Assunto , Pleiotropia Genética , Humanos , Desequilíbrio de Ligação , Metabolismo dos Lipídeos/genética , Análise da Randomização Mendeliana , Redes e Vias Metabólicas/genética , Herança Multifatorial , Nectinas/genética , Nectinas/metabolismo , Países Baixos , Proteômica , RNA-Seq
5.
Nat Commun ; 11(1): 5116, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037222

RESUMO

Mammographic density (MD) phenotypes are strongly associated with breast cancer risk and highly heritable. In this GWAS meta-analysis of 24,192 women, we identify 31 MD loci at P < 5 × 10-8, tripling the number known to 46. Seventeen identified MD loci also are associated with breast cancer risk in an independent meta-analysis (P < 0.05). Mendelian randomization analyses show that genetic estimates of dense area (DA), nondense area (NDA), and percent density (PD) are all significantly associated with breast cancer risk (P < 0.05). Pathway analyses reveal distinct biological processes involving DA, NDA and PD loci. These findings provide additional insights into the genetic basis of MD phenotypes and their associations with breast cancer risk.


Assuntos
Densidade da Mama , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/genética , Predisposição Genética para Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudo de Associação Genômica Ampla , Humanos , Mamografia , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
6.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 2346-2352, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018478

RESUMO

Lung cancer is a major public health burden and among the highest incidence and mortality rates of the cancers. MicroRNAs (miRNAs) play an important role in the development of lung cancer. The aim of this study was to investigate whether there was a potential causal relation between miRNAs and non-small-cell lung cancer (NSCLC). 1,026 patients with NSCLC from The Cancer Genome Atlas (TCGA) were analyzed. NSCLC associated SNPs' allele scores were established, and candidate miRNAs were filtered from differential expression analysis. Mendelian randomization (MR) analysis was conducted for 5 candidate miRNA (hsa-miR-135b, hsa-miR-142, hsa-miR-182, hsa-miR-183 and hsa-miR-3607) and 76 candidate SNPs in lung adenocarcinoma (LUAD) group. According to the core assumptions of MR, there was no clear evidence of a causal relation between the 5 candidate miRNAs and LUAD. The reads per million miRNAs mapped (RPM) level of candidate miRNAs changed less than 3% per allele score. To our knowledge, this is the first study using the TCGA data set to investigate the causal relation between miRNAs and lung cancer using the MR approach, and also one of the first MR studies to use miRNA expression as an exposure factor, with the SNPs as instrumental variables.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Análise da Randomização Mendeliana , MicroRNAs/genética , Nucleotídeos , Polimorfismo de Nucleotídeo Único
7.
BMC Med Genet ; 21(1): 178, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32912153

RESUMO

BACKGROUND: A Genetic risk score for coronary artery disease (CAD) improves the ability of predicting coronary heart disease (CHD). It is unclear whether i) the use of a CAD genetic risk score is superior to the measurement of coronary artery calcification (CAC) for CHD risk assessment and ii) the CHD risk assessment using a CAD genetic risk score differs between men and women. METHODS: We included 4041 participants (age-range: 45-76 years, 1919 men) of the Heinz Nixdorf Recall study without CHD or stroke at baseline. A standardized weighted CAD genetic risk score was constructed using 70 known genetic variants. The risk score was divided into quintiles (Q1-Q5). We specified low (Q1), intermediate (Q2-Q4) and high (Q5) genetic risk groups. Incident CHD was defined as fatal and non-fatal myocardial infarction, stroke and coronary death. The association between the genetic risk score and genetic risk groups with incident CHD was assessed using Cox models to estimate hazard ratios (HR) and 95%-confidence intervals (CI). The models were adjusted by age and sex (Model1), as well as by established CHD risk factors (RF) and CAC (Model2). The analyses were further stratified by sex and controlled for multiple testing. RESULTS: During a median follow-up time of 11.6 ± 3.7 years, 343 participants experienced CHD events (219 men). Per-standard deviation (SD) increase in the genetic risk score was associated with 18% increased risk for incident CHD (Model1: p = 0.002) which did not change after full adjustment (Model2: HR = 1.18 per-SD (p = 0.003)). In Model2 we observed a 60% increased CHD risk in the high (p = 0.009) compared to the low genetic risk group. Stratifying by sex, only men showed statistically significantly higher risk for CHD (Model2: HR = 1.23 per-SD (p = 0.004); intermediate: HR = 1.52 (p = 0.04) and high: HR = 1.88 (p = 0.008)) with no statistically significant risk observed in women. CONCLUSION: Our results suggest that the CAD genetic risk score could be useful for CHD risk prediction, at least in men belonging to the higher genetic risk group, but it does not outbalance the value of CT-based quantification of CAC which works independently on both men and women and allows better risk stratification in both the genders.


Assuntos
Doença da Artéria Coronariana/genética , Infarto do Miocárdio/genética , Medição de Risco/estatística & dados numéricos , Acidente Vascular Cerebral/genética , Idoso , Doença da Artéria Coronariana/diagnóstico , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Prognóstico , Modelos de Riscos Proporcionais , Medição de Risco/métodos , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Tomografia Computadorizada por Raios X
9.
Zhonghua Liu Xing Bing Xue Za Zhi ; 41(8): 1231-1236, 2020 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-32867428

RESUMO

Genetic variation is used as instrumental variable to investigate the causal relationship between exposure and outcome, which can avoid issues of confounding and reserve causation regarding Mendelian randomization studies. However, the instrumental variables in Mendelian randomization studies must satisfy three core assumptions-the relevance assumption, the independence assumption, and the exclusion restriction assumption. In addition to the plausibility of core assumptions, the application of Mendelian randomization studies in causal inference is also subject to other limitations. Findings from the Mendelian randomization studies should be interpreted in the context of existing evidence from other sources. In this article we provide an overview of the assumptions, limitations, and interpretation on causal inference that related to Mendelian randomization studies that can be applied in studies of the same kind.


Assuntos
Causalidade , Análise da Randomização Mendeliana , Variação Genética , Humanos
10.
PLoS Med ; 17(9): e1003302, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32915777

RESUMO

BACKGROUND: A number of epidemiological and genetic studies have attempted to determine whether levels of circulating lipids are associated with risks of various cancers, including breast cancer (BC). However, it remains unclear whether a causal relationship exists between lipids and BC. If alteration of lipid levels also reduced risk of BC, this could present a target for disease prevention. This study aimed to assess a potential causal relationship between genetic variants associated with plasma lipid traits (high-density lipoprotein, HDL; low-density lipoprotein, LDL; triglycerides, TGs) with risk for BC using Mendelian randomization (MR). METHODS AND FINDINGS: Data from genome-wide association studies in up to 215,551 participants from the Million Veteran Program (MVP) were used to construct genetic instruments for plasma lipid traits. The effect of these instruments on BC risk was evaluated using genetic data from the BCAC (Breast Cancer Association Consortium) based on 122,977 BC cases and 105,974 controls. Using MR, we observed that a 1-standard-deviation genetically determined increase in HDL levels is associated with an increased risk for all BCs (HDL: OR [odds ratio] = 1.08, 95% confidence interval [CI] = 1.04-1.13, P < 0.001). Multivariable MR analysis, which adjusted for the effects of LDL, TGs, body mass index (BMI), and age at menarche, corroborated this observation for HDL (OR = 1.06, 95% CI = 1.03-1.10, P = 4.9 × 10-4) and also found a relationship between LDL and BC risk (OR = 1.03, 95% CI = 1.01-1.07, P = 0.02). We did not observe a difference in these relationships when stratified by breast tumor estrogen receptor (ER) status. We repeated this analysis using genetic variants independent of the leading association at core HDL pathway genes and found that these variants were also associated with risk for BCs (OR = 1.11, 95% CI = 1.06-1.16, P = 1.5 × 10-6), including locus-specific associations at ABCA1 (ATP Binding Cassette Subfamily A Member 1), APOE-APOC1-APOC4-APOC2 (Apolipoproteins E, C1, C4, and C2), and CETP (Cholesteryl Ester Transfer Protein). In addition, we found evidence that genetic variation at the ABO locus is associated with both lipid levels and BC. Through multiple statistical approaches, we minimized and tested for the confounding effects of pleiotropy and population stratification on our analysis; however, the possible existence of residual pleiotropy and stratification remains a limitation of this study. CONCLUSIONS: We observed that genetically elevated plasma HDL and LDL levels appear to be associated with increased BC risk. Future studies are required to understand the mechanism underlying this putative causal relationship, with the goal of developing potential therapeutic strategies aimed at altering the cholesterol-mediated effect on BC risk.


Assuntos
Neoplasias da Mama/genética , Lipídeos/análise , Lipídeos/sangue , Adulto , Neoplasias da Mama/metabolismo , Colesterol/análise , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Análise da Randomização Mendeliana/métodos , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Triglicerídeos/sangue
11.
Yi Chuan ; 42(9): 882-888, 2020 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-32952122

RESUMO

Recent epidemiological studies suggest an association between shorter telomere length and higher risk for type 2 diabetes (T2D). However, results from observational studies are susceptible to confounding and reverse causation, and it is not clear whether there is a causal association between telomere length and T2D. Using Mendelian randomization (MR) and polygenic risk score (PRS) approaches, we had evaluated the causal effect of telomere length on T2D in the Chinese Han population. Using 8 telomere-length associated genetic variants as instrumental variables, an analysis of genetically predicted telomere length and T2D risk was performed in the MR study based on data from a T2D genome-wide association study (GWAS) in 2632 individuals (1318 cases and 1314 controls). We also applied a PRS approach to investigate the causal relationship using Chinese GWAS data. The inverse-variance weighted, MR-Egger regression, simple median, and weighted median methods yielded no evidence of association between genetically predicted longer telomere length and risk of T2D (OR = 0.78, 95% CI: 0.36 ~ 1.68, P = 0.522; OR = 0.23, 95% CI: 0.01 ~ 7.64, P = 0.412; OR = 0.60, 95% CI: 0.28 ~ 1.28, P = 0.185; OR = 0.64, 95% CI: 0.31 ~ 1.33,P = 0.233; respectively). Further, PRS analysis did not produce consistent genetic overlap between telomere length and T2D. Accordingly, this study found no evidence supporting a causal association between telomere length and T2D. Further studies with larger cohorts could yield more reliable results and conclusions.


Assuntos
Diabetes Mellitus Tipo 2 , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Telômero
12.
Neurology ; 95(14): e1963-e1970, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32817390

RESUMO

OBJECTIVE: To explore the causal relationships between sleep, major depressive disorder (MDD), and Alzheimer disease (AD). METHODS: We conducted bidirectional 2-sample Mendelian randomization analyses. Genetic associations were obtained from the largest genome-wide association studies currently available in UK Biobank (n = 446,118), Psychiatric Genomics Consortium (n = 18,759), and International Genomics of Alzheimer's Project (n = 63,926). We used the inverse variance-weighted Mendelian randomization method to estimate causal effects and weighted median and Mendelian randomization-Egger for sensitivity analyses to test for pleiotropic effects. RESULTS: We found that higher risk of AD was significantly associated with being a "morning person" (odds ratio [OR] 1.01, p = 0.001), shorter sleep duration (self-reported: ß = -0.006, p = 1.9 × 10-4; accelerometer based: ß = -0.015, p = 6.9 × 10-5), less likely to report long sleep (ß = -0.003, p = 7.3 × 10-7), earlier timing of the least active 5 hours (ß = -0.024, p = 1.7 × 10-13), and a smaller number of sleep episodes (ß = -0.025, p = 5.7 × 10-14) after adjustment for multiple comparisons. We also found that higher risk of AD was associated with lower risk of insomnia (OR 0.99, p = 7 × 10-13). However, we did not find evidence that these abnormal sleep patterns were causally related to AD or for a significant causal relationship between MDD and risk of AD. CONCLUSION: We found that AD may causally influence sleep patterns. However, we did not find evidence supporting a causal role of disturbed sleep patterns for AD or evidence for a causal relationship between MDD and AD.


Assuntos
Doença de Alzheimer/epidemiologia , Transtorno Depressivo Maior/epidemiologia , Sono , Doença de Alzheimer/genética , Transtorno Depressivo Maior/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Fenótipo , Sono/genética
13.
Nat Commun ; 11(1): 3981, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769997

RESUMO

Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors.


Assuntos
Pleiotropia Genética , Estudo de Associação Genômica Ampla , Neoplasias da Glândula Tireoide/genética , Tireotropina/genética , Loci Gênicos , Predisposição Genética para Doença , Bócio/genética , Humanos , Análise da Randomização Mendeliana , Herança Multifatorial/genética , Mutação de Sentido Incorreto/genética , Fenótipo , Mapeamento Físico do Cromossomo , Prevalência , Fatores de Risco , Tireoglobulina/genética , Neoplasias da Glândula Tireoide/epidemiologia
14.
Am J Psychiatry ; 177(10): 944-954, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32791893

RESUMO

OBJECTIVE: Efforts to prevent depression, the leading cause of disability worldwide, have focused on a limited number of candidate factors. Using phenotypic and genomic data from over 100,000 UK Biobank participants, the authors sought to systematically screen and validate a wide range of potential modifiable factors for depression. METHODS: Baseline data were extracted for 106 modifiable factors, including lifestyle (e.g., exercise, sleep, media, diet), social (e.g., support, engagement), and environmental (e.g., green space, pollution) variables. Incident depression was defined as minimal depressive symptoms at baseline and clinically significant depression at follow-up. At-risk individuals for incident depression were identified by polygenic risk scores or by reported traumatic life events. An exposure-wide association scan was conducted to identify factors associated with incident depression in the full sample and among at-risk individuals. Two-sample Mendelian randomization was then used to validate potentially causal relationships between identified factors and depression. RESULTS: Numerous factors across social, sleep, media, dietary, and exercise-related domains were prospectively associated with depression, even among at-risk individuals. However, only a subset of factors was supported by Mendelian randomization evidence, including confiding in others (odds ratio=0.76, 95% CI=0.67, 0.86), television watching time (odds ratio=1.09, 95% CI=1.05, 1.13), and daytime napping (odds ratio=1.34, 95% CI=1.17, 1.53). CONCLUSIONS: Using a two-stage approach, this study validates several actionable targets for preventing depression. It also demonstrates that not all factors associated with depression in observational research may translate into robust targets for prevention. A large-scale exposure-wide approach combined with genetically informed methods for causal inference may help prioritize strategies for multimodal prevention in psychiatry.


Assuntos
Depressão/prevenção & controle , Adulto , Bases de Dados como Assunto , Depressão/etiologia , Depressão/genética , Dieta , Exercício Físico/psicologia , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana , Herança Multifatorial/genética , Fatores de Risco , Tempo de Tela , Higiene do Sono
15.
Nat Commun ; 11(1): 3861, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737316

RESUMO

Integrating results from genome-wide association studies (GWASs) and gene expression studies through transcriptome-wide association study (TWAS) has the potential to shed light on the causal molecular mechanisms underlying disease etiology. Here, we present a probabilistic Mendelian randomization (MR) method, PMR-Egger, for TWAS applications. PMR-Egger relies on a MR likelihood framework that unifies many existing TWAS and MR methods, accommodates multiple correlated instruments, tests the causal effect of gene on trait in the presence of horizontal pleiotropy, and is scalable to hundreds of thousands of individuals. In simulations, PMR-Egger provides calibrated type I error control for causal effect testing in the presence of horizontal pleiotropic effects, is reasonably robust under various types of model misspecifications, is more powerful than existing TWAS/MR approaches, and can directly test for horizontal pleiotropy. We illustrate the benefits of PMR-Egger in applications to 39 diseases and complex traits obtained from three GWASs including the UK Biobank.


Assuntos
Pleiotropia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Análise da Randomização Mendeliana/estatística & dados numéricos , Modelos Genéticos , Transcriptoma , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Simulação por Computador , Bases de Dados Factuais , Gastroenteropatias/diagnóstico , Gastroenteropatias/genética , Gastroenteropatias/patologia , Humanos , Doenças do Sistema Imunitário/diagnóstico , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/patologia , Funções Verossimilhança , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/genética , Doenças Metabólicas/patologia , Herança Multifatorial , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/patologia , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia
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