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1.
BMJ Open ; 10(10): e038794, 2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33130567

RESUMO

OBJECTIVES: The overall aim of this study is to gain greater knowledge about the risk of suicide among suicide attempters in a very long-term perspective. Specifically, to investigate possible differences in clinical risk factors at short (≤5 years) versus long term (>5 years), with the hypothesis that risk factors differ in the shorter and longer perspective. DESIGN: Prospective study with register-based follow-up for 21-32 years. SETTING: Medical emergency inpatient unit in the south of Sweden. PARTICIPANTS: 1044 individuals assessed by psychiatric consultation when admitted to medical inpatient care for attempted suicide during 1987-1998. OUTCOME MEASURES: Suicide and all-cause mortality. RESULTS: At follow-up, 37.6% of the participants had died, 7.2% by suicide and 53% of these within 5 years of the suicide attempt. A diagnosis of psychosis at baseline represented the risk factor with the highest HR at long-term follow-up, that is, >5 years, followed by major depression and a history of attempted suicide before the index attempt. The severity of a suicide attempt as measured by SIS (Suicide Intent Scale) showed a non-proportional association with the hazard for suicide over time and was a relevant risk factor for suicide only within the first 5 years after an attempted suicide. CONCLUSIONS: The risk of suicide after a suicide attempt persists for up to 32 years after the index attempt. A baseline diagnosis of psychosis or major depression or earlier suicide attempts continued to be relevant risk factors in the very long term. The SIS score is a better predictor of suicide risk at short term, that is, within 5 years than at long term. This should be considered in the assessment of suicide risk and the implementation of care for these individuals.

2.
Am J Epidemiol ; 2020 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-32639533

RESUMO

Previous studies suggest that the association between mammographic density (MD) and breast cancer risk may be modified by other breast cancer risk factors. In this study, we assessed multiplicative interactions between MD measures and established risk factors on the risk of invasive breast cancer overall and by menopausal and estrogen receptor (ER) status. We used data on 2,137 cases and 4,346 controls from a nested case-control study within the Nurses' Health Studies I (1976-2004) and II (1989-2007), for whose data on percent mammographic density (PMD), absolute area of dense tissue (DA) and non-dense tissue (NDA) were available. No interaction remained statistically significant after adjusting for number of comparisons. For breast cancer overall, we observed nominally significant interactions (P < 0.05) between nulliparity and PMD/NDA, age at menarche and DA, and body mass index (BMI) and NDA. Individual nominally significant interactions across MD measures and risk factors were also observed in analyses stratified by either menopausal or ER status. Our findings help provide further insights into potential mechanisms underlying the association between MD and breast cancer.

3.
J Natl Cancer Inst ; 2020 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-32359158

RESUMO

We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72,284 cases and 80,354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression, and a newly developed case-only method, for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history), and on average 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.

4.
Nord J Psychiatry ; 74(6): 429-438, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32129114

RESUMO

Background: The Self-Harm Antipathy Scale (SHAS) is a questionnaire designed to measure nurses' attitudes towards self-harm. This can be useful to improve the quality of care provided to individuals who self-harm.Aim: The purpose of this study was to revise and adapt the SHAS for use in Sweden and evaluate the psychometric properties of this Swedish version (Self-Harm Antipathy Scale - Swedish Revised; SHAS-SR).Methods: A sample of 596 employees within psychiatric healthcare was recruited (from a total of 3507, response rate 17.0%), the majority encountering self-harming individuals regularly at work. Participants completed the SHAS-SR questionnaire along with a scale assessing community attitudes towards individuals with mental illness (New CAMI-S). The sample was randomly split in half (n = 298 each). Exploratory factor analysis was performed on one subsample and confirmatory on the other. Confirmatory factor analysis on the original SHAS model, and convergent validity testing against New CAMI-S, used the whole sample.Results: The final version of the SHAS-SR included 17 items forming three factors. Convergent validity was established (r = -0.57, ρ = -0.48, p < 0.001). The SHAS-SR and all its subscales demonstrated acceptable internal consistency (α = 0.73-0.79, ω = 0.78-0.79).Conclusion: This study indicates that the SHAS-SR is reliable and valid when assessing attitudes towards self-harm among a sample of Swedish psychiatric healthcare staff. The scale could be useful for assessing the impact of attitude interventions to improve healthcare services. It may, however, have limited applicability for staff not working in caring roles.


Assuntos
Atitude do Pessoal de Saúde , Pessoal de Saúde/psicologia , Pessoal de Saúde/normas , Comportamento Autodestrutivo/epidemiologia , Comportamento Autodestrutivo/psicologia , Inquéritos e Questionários/normas , Adulto , Feminino , Humanos , Masculino , Transtornos Mentais/diagnóstico , Transtornos Mentais/epidemiologia , Transtornos Mentais/psicologia , Pessoa de Meia-Idade , Relações Enfermeiro-Paciente , Psicometria , Reprodutibilidade dos Testes , Comportamento Autodestrutivo/diagnóstico , Suécia
6.
Cancer Causes Control ; 31(3): 273-282, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32006205

RESUMO

PURPOSE: The relationship of allergic diseases, such as asthma, hay fever, and eczema, with cancer is under debate. Observational studies have reported conflicting findings, but such studies are susceptible to confounding and reverse causation. Understanding the potential role of allergy in carcinogenesis may shed new light on the biological mechanisms underpinning intrinsic immunity and cancer. METHODS: We conducted a Mendelian randomization study, using germline genetic variants as instrumental variables, to determine the causal relevance of allergic disease and on two most common malignancies: breast cancer and prostate cancer. We used the summary statistics from the largest ever genome-wide association studies conducted on allergic disease (ncase = 180,129), asthma (ncase = 14,085), breast (ncase = 122,977), and prostate cancer (ncase = 79,148) and calculated odds ratios (ORs) and 95% confidence intervals (CIs) of cancer for allergic disease. RESULTS: We did not observe any evidence to support a causal association between allergic disease and risk of breast cancer overall [OR 1.00 (95% CI 0.96-1.04), p = 0.95] or by subtype (estrogen receptor (ER)+ [0.99 (0.95-1.04), p = 0.71], ER- [1.05 (0.99-1.10), p = 0.11]). We also did not find any evidence for an association with prostate cancer [1.00 (0.94-1.05), p = 0.93] or advanced subtype [0.97 (0.90-1.05), p = 0.46]. Sensitivity analyses did not reveal directional pleiotropy. CONCLUSION: Our study does not support a causal effect of allergic disease on the risk of breast or prostate cancer. Future studies may be conducted to focus on understanding the causal role of allergic disease in cancer prognosis or drug responses (e.g., immunotherapy).


Assuntos
Asma/complicações , Neoplasias da Mama/imunologia , Neoplasias da Próstata/imunologia , Asma/genética , Neoplasias da Mama/genética , Estudos de Casos e Controles , Suscetibilidade a Doenças , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Razão de Chances , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética
7.
Int J Epidemiol ; 49(1): 216-232, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31605532

RESUMO

BACKGROUND: Previous gene-environment interaction studies of breast cancer risk have provided sparse evidence of interactions. Using the largest available dataset to date, we performed a comprehensive assessment of potential effect modification of 205 common susceptibility variants by 13 established breast cancer risk factors, including replication of previously reported interactions. METHODS: Analyses were performed using 28 176 cases and 32 209 controls genotyped with iCOGS array and 44 109 cases and 48 145 controls genotyped using OncoArray from the Breast Cancer Association Consortium (BCAC). Gene-environment interactions were assessed using unconditional logistic regression and likelihood ratio tests for breast cancer risk overall and by estrogen-receptor (ER) status. Bayesian false discovery probability was used to assess the noteworthiness of the meta-analysed array-specific interactions. RESULTS: Noteworthy evidence of interaction at ≤1% prior probability was observed for three single nucleotide polymorphism (SNP)-risk factor pairs. SNP rs4442975 was associated with a greater reduction of risk of ER-positive breast cancer [odds ratio (OR)int = 0.85 (0.78-0.93), Pint = 2.8 x 10-4] and overall breast cancer [ORint = 0.85 (0.78-0.92), Pint = 7.4 x 10-5) in current users of estrogen-progesterone therapy compared with non-users. This finding was supported by replication using OncoArray data of the previously reported interaction between rs13387042 (r2 = 0.93 with rs4442975) and current estrogen-progesterone therapy for overall disease (Pint = 0.004). The two other interactions suggested stronger associations between SNP rs6596100 and ER-negative breast cancer with increasing parity and younger age at first birth. CONCLUSIONS: Overall, our study does not suggest strong effect modification of common breast cancer susceptibility variants by established risk factors.

8.
Am J Epidemiol ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31712804

RESUMO

Hepatitis C virus (HCV) is common among people living with human immunodeficiency virus (PLWH). Extrahepatic manifestations of HCV, including myocardial infarction (MI), are a topic of active research. MI is classified into types, predominantly atheroembolic Type 1 MI (T1MI) and supply-demand mismatch Type 2 MI (T2MI). We examined the association between HCV and MI in the Centers for Acquired Immunodeficiency Syndrome Research Network of Integrated Clinical Systems, a multi-center clinical cohort of PLWH. MIs were centrally adjudicated and categorized by type using the Universal MI definition. We estimated the association between chronic HCV (RNA+) and time to MI adjusting for demographic characteristics, cardiovascular risk factors, clinical characteristics and history of injecting drug use. Among 23,407 PLWH aged ≥18, there were 336 T1MI and 330 T2MI during a median of 4.7 years of follow-up during 1998 through 2016. HCV was associated with a 46% greater risk of T2MI (adjusted hazard ratio (aHR) 1.46, 95% CI: 1.09, 1.97) but not T1MI (aHR 0.87, 95% CI: 0.58, 1.29). In an exploratory cause-specific analysis of T2MI, HCV was associated with a 2-fold greater risk of T2MI attributed to sepsis (aHR 2.01, 95% CI: 1.25, 3.24). Extrahepatic manifestations of HCV in this high-risk population are an important area for continued research.

9.
Circ Genom Precis Med ; 12(12): e002711, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31756303

RESUMO

BACKGROUND: Evidence from randomized trials has shown that therapies that lower LDL (low-density lipoprotein)-cholesterol and triglycerides reduce coronary artery disease (CAD) risk. However, there is still uncertainty about their effects on other cardiovascular outcomes. We therefore performed a systematic investigation of causal relationships between circulating lipids and cardiovascular outcomes using a Mendelian randomization approach. METHODS: In the primary analysis, we performed 2-sample multivariable Mendelian randomization using data from participants of European ancestry. We also conducted univariable analyses using inverse-variance weighted and robust methods, and gene-specific analyses using variants that can be considered as proxies for specific lipid-lowering medications. We obtained associations with lipid fractions from the Global Lipids Genetics Consortium, a meta-analysis of 188 577 participants, and genetic associations with cardiovascular outcomes from 367 703 participants in UK Biobank. RESULTS: For LDL-cholesterol, in addition to the expected positive associations with CAD risk (odds ratio [OR] per 1 SD increase, 1.45 [95% CI, 1.35-1.57]) and other atheromatous outcomes (ischemic cerebrovascular disease and peripheral vascular disease), we found independent associations of genetically predicted LDL-cholesterol with abdominal aortic aneurysm (OR, 1.75 [95% CI, 1.40-2.17]) and aortic valve stenosis (OR, 1.46 [95% CI, 1.25-1.70]). Genetically predicted triglyceride levels were positively associated with CAD (OR, 1.25 [95% CI, 1.12-1.40]), aortic valve stenosis (OR, 1.29 [95% CI, 1.04-1.61]), and hypertension (OR, 1.17 [95% CI, 1.07-1.27]), but inversely associated with venous thromboembolism (OR, 0.79 [95% CI, 0.67-0.93]) and hemorrhagic stroke (OR, 0.78 [95% CI, 0.62-0.98]). We also found positive associations of genetically predicted LDL-cholesterol and triglycerides with heart failure that appeared to be mediated by CAD. CONCLUSIONS: Lowering LDL-cholesterol is likely to prevent abdominal aortic aneurysm and aortic stenosis, in addition to CAD and other atheromatous cardiovascular outcomes. Lowering triglycerides is likely to prevent CAD and aortic valve stenosis but may increase thromboembolic risk.

10.
Nat Genet ; 51(11): 1574-1579, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31676865

RESUMO

Venous thromboembolism is a significant cause of mortality1, yet its genetic determinants are incompletely defined. We performed a discovery genome-wide association study in the Million Veteran Program and UK Biobank, with testing of approximately 13 million DNA sequence variants for association with venous thromboembolism (26,066 cases and 624,053 controls) and meta-analyzed both studies, followed by independent replication with up to 17,672 venous thromboembolism cases and 167,295 controls. We identified 22 previously unknown loci, bringing the total number of venous thromboembolism-associated loci to 33, and subsequently fine-mapped these associations. We developed a genome-wide polygenic risk score for venous thromboembolism that identifies 5% of the population at an equivalent incident venous thromboembolism risk to carriers of the established factor V Leiden p.R506Q and prothrombin G20210A mutations. Our data provide mechanistic insights into the genetic epidemiology of venous thromboembolism and suggest a greater overlap among venous and arterial cardiovascular disease than previously thought.


Assuntos
Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Doenças Vasculares/genética , Tromboembolia Venosa/genética , Idoso , Animais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/genética , Fatores de Risco , Reino Unido/epidemiologia , Doenças Vasculares/epidemiologia , Doenças Vasculares/patologia , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/patologia
11.
Blood ; 134(19): 1645-1657, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31420334

RESUMO

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.


Assuntos
Predisposição Genética para Doença/genética , Tromboembolia Venosa/genética , Estudo de Associação Genômica Ampla , Humanos
12.
Hum Genet ; 138(10): 1091-1104, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31230194

RESUMO

Although genome-wide association studies (GWAS) have identified hundreds of risk loci for breast and prostate cancer, only a few studies have characterized the GWAS association signals across functional genomic annotations with a particular focus on single nucleotide polymorphisms (SNPs) located in DNA regulatory elements. In this study, we investigated the enrichment pattern of GWAS signals for breast and prostate cancer in genomic functional regions located in normal tissue and cancer cell lines. We quantified the overall enrichment of SNPs with breast and prostate cancer association p values < 1 × 10-8 across regulatory categories. We then obtained annotations for DNaseI hypersensitive sites (DHS), typical enhancers, and super enhancers across multiple tissue types, to assess if significant GWAS signals were selectively enriched in annotations found in disease-related tissue. Finally, we quantified the enrichment of breast and prostate cancer SNP heritability in regulatory regions, and compared the enrichment pattern of SNP heritability with GWAS signals. DHS, typical enhancers, and super enhancers identified in the breast cancer cell line MCF-7 were observed with the highest enrichment of genome-wide significant variants for breast cancer. For prostate cancer, GWAS signals were mostly enriched in DHS and typical enhancers identified in the prostate cancer cell line LNCaP. With progressively stringent GWAS p value thresholds, an increasing trend of enrichment was observed for both diseases in DHS, typical enhancers, and super enhancers located in disease-related tissue. Results from heritability enrichment analysis supported the selective enrichment pattern of functional genomic regions in disease-related cell lines for both breast and prostate cancer. Our results suggest the importance of studying functional annotations identified in disease-related tissues when characterizing GWAS results, and further demonstrate the role of germline DNA regulatory elements from disease-related tissue in breast and prostate carcinogenesis.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Variação Genética , Neoplasias da Próstata/genética , Sequências Reguladoras de Ácido Nucleico , Biomarcadores Tumorais , Linhagem Celular Tumoral , Biologia Computacional/métodos , Feminino , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Anotação de Sequência Molecular , Especificidade de Órgãos
13.
Int J Epidemiol ; 48(3): 822-830, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31211375

RESUMO

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with an estimated prevalence of 4-21% in reproductive aged women. Recently, the Ovarian Cancer Association Consortium (OCAC) reported a decreased risk of invasive ovarian cancer among women with self-reported PCOS. However, given the limitations of self-reported PCOS, the validity of these observed associations remains uncertain. Therefore, we sought to use Mendelian randomization with genetic markers as a proxy for PCOS, to examine the association between PCOS and ovarian cancer. METHODS: Utilizing 14 single nucleotide polymorphisms (SNPs) previously associated with PCOS we assessed the association between genetically predicted PCOS and ovarian cancer risk, overall and by histotype, using summary statistics from a previously conducted genome-wide association study (GWAS) of ovarian cancer among European ancestry women within the OCAC (22 406 with invasive disease, 3103 with borderline disease and 40 941 controls). RESULTS: An inverse association was observed between genetically predicted PCOS and invasive ovarian cancer risk: odds ratio (OR)=0.92 [95% confidence interval (CI)=0.85-0.99; P = 0.03]. When results were examined by histotype, the strongest inverse association was observed between genetically predicted PCOS and endometrioid tumors (OR = 0.77; 95% CI = 0.65-0.92; P = 0.003). Adjustment for individual-level body mass index, oral contraceptive use and parity did not materially change the associations. CONCLUSION: Our study provides evidence for a relationship between PCOS and reduced ovarian cancer risk, overall and among specific histotypes of invasive ovarian cancer. These results lend support to our previous observational study results. Future studies are needed to understand mechanisms underlying this association.


Assuntos
Adenocarcinoma de Células Claras/epidemiologia , Adenocarcinoma Mucinoso/epidemiologia , Carcinoma Endometrioide/epidemiologia , Neoplasias Ovarianas/epidemiologia , Síndrome do Ovário Policístico/epidemiologia , Feminino , Humanos , Análise da Randomização Mendeliana , Neoplasias Císticas, Mucinosas e Serosas/epidemiologia , Síndrome do Ovário Policístico/genética
14.
Breast Cancer Res ; 21(1): 68, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118087

RESUMO

BACKGROUND: Mammographic breast density, adjusted for age and body mass index, and a polygenic risk score (PRS), comprised of common genetic variation, are both strong risk factors for breast cancer and increase discrimination of risk models. Understanding their joint contribution will be important to more accurately predict risk. METHODS: Using 3628 breast cancer cases and 5126 controls of European ancestry from eight case-control studies, we evaluated joint associations of a 77-single nucleotide polymorphism (SNP) PRS and quantitative mammographic density measures with breast cancer. Mammographic percent density and absolute dense area were evaluated using thresholding software and examined as residuals after adjusting for age, 1/BMI, and study. PRS and adjusted density phenotypes were modeled both continuously (per 1 standard deviation, SD) and categorically. We fit logistic regression models and tested the null hypothesis of multiplicative joint associations for PRS and adjusted density measures using likelihood ratio and global and tail-based goodness of fit tests within the subset of six cohort or population-based studies. RESULTS: Adjusted percent density (odds ratio (OR) = 1.45 per SD, 95% CI 1.38-1.52), adjusted absolute dense area (OR = 1.34 per SD, 95% CI 1.28-1.41), and the 77-SNP PRS (OR = 1.52 per SD, 95% CI 1.45-1.59) were associated with breast cancer risk. There was no evidence of interaction of the PRS with adjusted percent density or dense area on risk of breast cancer by either the likelihood ratio (P > 0.21) or goodness of fit tests (P > 0.09), whether assessed continuously or categorically. The joint association (OR) was 2.60 in the highest categories of adjusted PD and PRS and 0.34 in the lowest categories, relative to women in the second density quartile and middle PRS quintile. CONCLUSIONS: The combined associations of the 77-SNP PRS and adjusted density measures are generally well described by multiplicative models, and both risk factors provide independent information on breast cancer risk.


Assuntos
Biomarcadores Tumorais , Densidade da Mama/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Herança Multifatorial , Adulto , Idoso , Algoritmos , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Modelos Biológicos , Razão de Chances , Polimorfismo de Nucleotídeo Único , Medição de Risco , Fatores de Risco
15.
PLoS One ; 14(5): e0216997, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31125336

RESUMO

PURPOSE: Genome-wide-association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) that are associated with an increased risk of breast cancer. Most of these studies were conducted primarily in postmenopausal breast cancer patients. Therefore, we set out to assess whether or not these breast cancer variants are also associated with an elevated risk of breast cancer in young premenopausal patients. METHODS: In 451 women of European ancestry who had prospectively enrolled in a longitudinal cohort study for women diagnosed with breast cancer at or under age 40, we genotyped 44 SNPs that were previously associated with breast cancer risk. A control group was comprised of 1142 postmenopausal healthy women from the Nurses' Health Study (NHS). We assessed if the frequencies of the adequately genotyped SNPs differed significantly (p≤0.05) between the cohort of young breast cancer patients and postmenopausal controls, and then we corrected for multiple testing. RESULTS: Genotyping of the controls or cases was inadequate for comparisons between the groups for seven of the 44 SNPs. 9 of the remaining 37 were associated with breast cancer risk in young women with a p-value <0.05: rs10510102, rs1219648, rs13387042, rs1876206, rs2936870, rs2981579, rs3734805, rs3803662 and rs4973768. The directions of these associations were consistent with those in postmenopausal women. However, after correction for multiple testing (Benjamini Hochberg) none of the results remained statistically significant. CONCLUSION: After correction for multiple testing, none of the alleles for postmenopausal breast cancer were clearly associated with risk of premenopausal breast cancer in this relatively small study.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Adulto , Alelos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Receptores Estrogênicos/genética , Fatores de Risco
16.
Nat Commun ; 10(1): 569, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718517

RESUMO

We introduce cross-trait penalized regression (CTPR), a powerful and practical approach for multi-trait polygenic risk prediction in large cohorts. Specifically, we propose a novel cross-trait penalty function with the Lasso and the minimax concave penalty (MCP) to incorporate the shared genetic effects across multiple traits for large-sample GWAS data. Our approach extracts information from the secondary traits that is beneficial for predicting the primary trait based on individual-level genotypes and/or summary statistics. Our novel implementation of a parallel computing algorithm makes it feasible to apply our method to biobank-scale GWAS data. We illustrate our method using large-scale GWAS data (~1M SNPs) from the UK Biobank (N = 456,837). We show that our multi-trait method outperforms the recently proposed multi-trait analysis of GWAS (MTAG) for predictive performance. The prediction accuracy for height by the aid of BMI improves from R2 = 35.8% (MTAG) to 42.5% (MCP + CTPR) or 42.8% (Lasso + CTPR) with UK Biobank data.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Modelos Genéticos , Algoritmos , Genótipo , Humanos , Fenótipo , Locos de Características Quantitativas/genética
17.
Genet Epidemiol ; 43(4): 449-457, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30659681

RESUMO

Although recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene-based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene-based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low-frequency and rare variants associated with VTE risk.


Assuntos
Exoma/genética , Estudo de Associação Genômica Ampla/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Análise em Microsséries/métodos , Tromboembolia Venosa/genética , Afro-Americanos/genética , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Humanos , Masculino , Análise em Microsséries/estatística & dados numéricos , Razão de Chances , Polimorfismo de Nucleotídeo Único , Tamanho da Amostra , Tromboembolia Venosa/etnologia
18.
Schizophr Bull ; 45(6): 1251-1256, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-30452727

RESUMO

Observational epidemiological studies have found an association between schizophrenia and breast cancer, but it is not known if the relationship is a causal one. We used summary statistics from very large genome-wide association studies of schizophrenia (n = 40675 cases and 64643 controls) and breast cancer (n = 122977 cases and 105974 controls) to investigate whether there is evidence that the association is partly due to shared genetic risk factors and whether there is evidence of a causal relationship. Using LD-score regression, we found that there is a small but significant genetic correlation (rG) between the 2 disorders (rG = 0.14, SE = 0.03, P = 4.75 × 10-8), indicating shared genetic risk factors. Using 142 genetic variants associated with schizophrenia as instrumental variables that are a proxy for having schizophrenia, we estimated a causal effect of schizophrenia on breast cancer on the observed scale as bxy = 0.032 (SE = 0.009, P = 2.3 × 10-4). A 1 SD increase in liability to schizophrenia increases risk of breast cancer 1.09-fold. In contrast, the estimated causal effect of breast cancer on schizophrenia from 191 instruments was not significantly different from zero (bxy = -0.005, SE = 0.012, P = .67). No evidence for pleiotropy was found and adjusting for the effects of smoking or parity did not alter the results. These results provide evidence that the previously observed association is due to schizophrenia causally increasing risk for breast cancer. Genetic variants may provide an avenue to elucidating the mechanism underpinning this relationship.

19.
J Am Heart Assoc ; 7(22): e010317, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30571496

RESUMO

Background Venous thromboembolism ( VTE ) is a complex thrombotic disorder that constitutes a major source of mortality and morbidity. To improve understanding of the cause of VTE , we conducted a metabolomic analysis in a case-control study including 240 incident VTE cases and 6963 controls nested within 3 large prospective population-based cohorts, the Nurses' Health Study, the Nurses' Health Study II , and the Health Professionals Follow-Up Study. Methods and Results For each individual, we measured 211 metabolites and collected detailed information on lifestyle factors. We performed logistic regression and enrichment analysis to identify metabolites and biological categories associated with incident VTE risk, accounting for key confounders, such as age, sex, smoking, alcohol consumption, body mass index, and comorbid diseases (eg, cancers). We performed analyses of all VTEs and separate analyses of pulmonary embolism. Using the basic model controlling for age, sex, and primary disease, we identified 60 nominally significant VTE - or pulmonary embolism-associated metabolites ( P<0.05). These metabolites were enriched for diacylglycerols ( Ppermutation<0.05). However, after controlling for multiple testing, only 1 metabolite (C5 carnitine; odds ratio, 1.25; 95% confidence interval, 1.10-1.41; Pcorrected=0.03) remained significantly associated with VTE . After further adjustment for body mass index, no metabolites were significantly associated with disease after accounting for multiple testing, and no metabolite classes were enriched for nominally significant associations. Conclusions Although our findings suggest that circulating metabolites may influence the risk of incident VTE , the associations we observed were confounded by body mass index. Larger studies involving additional individuals and with broader metabolomics coverage are needed to confirm our findings.


Assuntos
Tromboembolia Venosa/etiologia , Fatores Etários , Consumo de Bebidas Alcoólicas/efeitos adversos , Índice de Massa Corporal , Carnitina/biossíntese , Estudos de Casos e Controles , Diglicerídeos/sangue , Feminino , Humanos , Modelos Logísticos , Masculino , Metabolômica , Pessoa de Meia-Idade , Fatores de Risco , Fatores Sexuais , Fumar/efeitos adversos , Tromboembolia Venosa/sangue , Tromboembolia Venosa/metabolismo
20.
Thromb Res ; 172: 67-73, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30384037

RESUMO

OBJECTIVE: Adult body mass index (BMI) is strongly associated with venous thromboembolism (VTE), however whether earlier-life adiposity or other measures of adult adiposity are associated with VTE risk remains largely unknown. MATERIALS AND METHODS: We evaluated associations of childhood somatotype, BMI in early adulthood, adult adiposity, and change in weight since early adulthood with incident VTE risk over ≥20 years of follow-up among 205,935 participants from Nurses' Health Studies (NHS/NHS II) and Health Professionals Follow-Up Study (HPFS), ages 29-76 at baseline. We estimated multivariable-adjusted hazard ratios for VTE using Cox proportional hazards models. RESULTS AND CONCLUSIONS: Somatotype in childhood and young adulthood BMI were not significantly associated with VTE risk, after accounting for adult BMI. Adult BMI was strongly associated with VTE in all three cohorts (e.g., multivariable-adjusted HRs comparing ≥35 kg/m2 vs. <22.5 kg/m2: NHS:3.03[95% CI: 2.58, 3.56], NHS II:3.82[95% CI: 3.24, 4.51], HPFS:2.81 [95% CI: 2.08, 3.80]; all p-trends < 0.01). Adult waist circumference was associated with greater VTE risk, even after adjusting for adult BMI (all p-trends < 0.01). Increasing weight gain from young adulthood was significantly associated with VTE after adjusting for current BMI among women (HR comparing gain ≥20 kg vs. no change: NHS:1.36[95% CI: 1.13, 1.65], NHS II:1.48[95% CI: 1.17, 1.87]) and not men (HPFS:1.20[95% CI: 0.97, 1.50]). These results indicate that BMI and adiposity are likely more important acutely than cumulatively over time in the etiology and prevention of VTE. Clinically, encouraging weight loss in individuals who are overweight or obese could help reduce VTE risk.


Assuntos
Adiposidade , Tromboembolia Venosa/etiologia , Adulto , Idoso , Índice de Massa Corporal , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Sobrepeso/complicações , Fatores de Risco , Tromboembolia Venosa/diagnóstico , Ganho de Peso , Adulto Jovem
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