Center for Medical Systems Biology

Leiden, Netherlands

Center for Medical Systems Biology

Leiden, Netherlands
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Isaacs A.,Erasmus Medical Center | Willems S.M.,Erasmus Medical Center | Arfan Ikram M.,Center for Medical Systems Biology | Uitterlinden A.G.,Erasmus Medical Center | And 3 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2013

Objective-Circulating levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides are recognized risk factors for cardiovascular disease. We tested the hypothesis that the cumulative effects of common genetic variants for lipids are collectively associated with subclinical atherosclerosis and incident coronary heart disease. Approach and Results-Participants were drawn from the Erasmus Rucphen Family Study (n=2269) and the Rotterdam Study (n=8130). Linear regression and Cox proportional hazards models were applied to assess the influence of 4 risk scores derived from common genetic variants for lipids (total cholesterol, LDL-C, high-density lipoprotein cholesterol, and triglycerides) on carotid plaque, intima-media thickness, incident myocardial infarction, and coronary heart disease. Adjusted for age and sex, all 4 risk scores were associated with carotid plaque. This relationship was the strongest for the LDL-C score, which increased plaque score by 0.102 per SD increase in genetic risk score (P=3.2×10). The LDL-C score was also nominally associated with intima-media thickness, which increased 0.006 mm per SD increase in score (P=0.05). Both the total cholesterol and LDL-C scores were associated with incident myocardial infarction and coronary heart disease with hazard ratios between 1.10 and 1.13 per SD increase in score. Inclusion of additional risk factors as covariates minimally affected these results. Conclusions-Common genetic variants with small effects on lipid levels are, in combination, significantly associated with subclinical and clinical cardiovascular outcomes. As knowledge of genetic variation increases, preclinical genetic screening tools might enhance the prediction and prevention of clinical events. © 2013 American Heart Association, Inc.


Lubke G.H.,University of Notre Dame | Lubke G.H.,VU University Amsterdam | Laurin C.,VU University Amsterdam | Amin N.,Erasmus Medical Center | And 14 more authors.
Molecular Psychiatry | Year: 2014

The heritability of borderline personality (BP) features has been established in multiple twin and family studies. Using data from the borderline subscale of the Personality Assessment Inventory Borderline Features Scale (PAI-BOR) collected in two Dutch cohorts (N=7125), the Netherlands Twin Register and The Netherlands Study of Depression and Anxiety, we show that heritability of the PAI-BOR total score using genome-wide single-nucleotide polymorphism (SNPs) is estimated at 23%, and that the genetic variance is substantially higher in affect instability items compared with the other three subscales of the PAI-BOR (42.7% vs non-significant estimates for self-harm, negative relations and identity problems). We present results from a first genome-wide association study of BP features, which shows a promising signal on chromosome 5 corresponding to SERINC5, a protein involved in myelination. Reduced myelination has been suggested as possibly having a role in the development of psychiatric disorders characterized by lack of social interaction. The signal was confirmed in a third independent Dutch cohort drawn from the Erasmus Rucphen Family study (N=1301). Our analyses were complemented by investigating the heterogeneity that was implied by the differences in genetic variance components in the four subscales of the PAI-BOR. These analyses show that the association of SNPs tagging SERINC5 differs substantially across the 24 items of the PAI-BOR. Further, using reverse regression we showed that the effects were present only in subjects with higher scores on the PAI-BOR. Taken together, these results suggest that future genome-wide analyses can benefit substantially by taking into account the phenotypic and genetic heterogeneity of BP features. © 2014 Macmillan Publishers Limited.


Brouwers M.C.G.J.,Maastricht University | Konrad R.J.,Eli Lilly and Company | van Himbergen T.M.,Tufts University | Isaacs A.,Erasmus Medical Center | And 8 more authors.
Nutrition, Metabolism and Cardiovascular Diseases | Year: 2013

Background and aims: Two recent independent studies showed that patients with familial combined hyperlipidemia (FCHL) have elevated plasma levels of proprotein convertase subtilisin kexin type 9 (PCSK9) and markers of cholesterol synthesis. Both PCSK9 expression and cholesterol synthesis are downstream effects of hepatic activation of sterol regulatory element binding protein 2 (SREBP2). The present study was conducted to study the relationship between plasma PCSK9 and markers of cholesterol synthesis in FCHL. Methods and results: Markers of cholesterol synthesis (squalene, desmosterol, lathosterol), cholesterol absorption (campesterol, sitosterol, cholestanol) and PCSK9 were measured in plasma of FCHL patients (n=103) and their normolipidemic relatives (NLR; n=240). Plasma PCSK9, lathosterol and desmosterol levels were higher in FCHL patients than their NLR (p<0.001, age and sex adjusted). Heritability calculations demonstrated that 35% of the variance in PCSK9 levels could be explained by additive genetic effects (p<0.001). Significant age- and sex-adjusted correlations were observed for the relationship between PCSK9 and lathosterol, both unadjusted and adjusted for cholesterol, in the overall FCHL population (both p<0.001). Multivariate regression analyses, with PCSK9 as the dependent variable, showed that the regression coefficient for FCHL status decreased by 25% (from 0.8 to 0.6) when lathosterol was included. Nevertheless, FCHL status remained an independent contributor to plasma PCSK9 (p<0.001). Conclusions: The present study confirms the previously reported high and heritable PCSK9 levels in FCHL patients. Furthermore, we now show that high PCSK9 levels are, in part, explained by plasma lathosterol, suggesting that SREBP2 activation partly accounts for elevated PCSK9 levels in FCHL. © 2012 Elsevier B.V.


Cornel M.C.,EMGO Institute for Health and Care Research | Cornel M.C.,Center for Medical Systems Biology | Cornel M.C.,Center for Society and Genomics | Van El C.G.,EMGO Institute for Health and Care Research | Dondorp W.J.,Maastricht University
Journal of Community Genetics | Year: 2012

New screening possibilities become available at a high rate, both useful and unsound possibilities. All screening programmes do harm, and only few have more advantages than disadvantages at reasonable cost. Horizon scanning is needed to identify those few possibilities with more pros than cons. Attunement is needed between actors involved: scientists developing new high-throughput screening techniques and treatment, health care workers, patients and consumers and governmental agencies. The product of a process of attunement may be a quality mark as a norm for professional conduct, rather than legal measures, as the field is moving fast. As actors may have varying perspectives, a governance structure is needed to develop an agenda that is agreed upon by all or most actors involved. A standing committee might oversee the evaluation of benefits and disadvantages in an integrated approach, taking evidence, economics and ethics into account. A proactive role of governmental agencies is needed to facilitate agenda setting and attunement. Policy making has to be transparent and open to stakeholder engagement. © The Author(s) 2011.


Schol-Gelok S.,Erasmus University Rotterdam | Janssens A.C.J.W.,Erasmus University Rotterdam | Tiemeier H.,Erasmus University Rotterdam | Liu F.,Erasmus University Rotterdam | And 11 more authors.
Biological Psychiatry | Year: 2010

Background: Depression has a strong genetic component but candidate gene studies conducted to date have not shown consistent associations. Methods: We conducted a genome-wide parametric and nonparametric linkage analysis in a large-scale family-based study including 115 individuals with depression who were identified based on the Hospital Anxiety Depression Scale, Center for Epidemiologic Studies Depression Rating Scale, or use of antidepressive medication. Further, we investigated the most promising chromosomal regions found in the genome-wide linkage analysis with an association analysis in 734 individuals in the family-based study and 2373 individuals in the population-based study. Results: Our study demonstrated evidence for significant linkage of depression to chromosome 2p16.1-15 (logarithm of odds [LOD]= 5.13; parametric analysis) and suggestive evidence for linkage in nonparametric analysis to chromosome 5p15.33 (LOD=2.14), 11q25 (LOD=2.27), and 19p13.3 (LOD=2.66). The subsequent association analysis in the family-based study showed region-wide significant association in intron 1 of the OPCML gene on chromosome 11q25 (empirical p value=.04). The association analysis in the population-based study did not show any region-wide significant association, yet showed suggestive association in intron 1 of the APLP2 gene on chromosome 11q25. Conclusions: Our linkage and association studies suggest a locus for depression on chromosomes 2p16.1-15 and 11q25. The linkage to chromosome 11q25 may be, in part, explained by the OPCML or the APLP2 gene. Further, there is evidence for a role of the GNG7 gene (chromosome 19p13.3). © 2010 Society of Biological Psychiatry.


Amin N.,Erasmus Medical Center | Schuur M.,Erasmus Medical Center | Gusareva E.S.,Academy of Sciences of the Czech Republic | Isaacs A.,Erasmus Medical Center | And 9 more authors.
Molecular Psychiatry | Year: 2012

The NEO-Five-Factor Inventory divides human personality traits into five dimensions: neuroticism, extraversion, openness, conscientiousness and agreeableness. In this study, we sought to identify regions harboring genes with large effects on the five NEO personality traits by performing genome-wide linkage analysis of individuals scoring in the extremes of these traits (90th percentile). Affected-only linkage analysis was performed using an Illumina 6K linkage array in a family-based study, the Erasmus Rucphen Family study. We subsequently determined whether distinct, segregating haplotypes found with linkage analysis were associated with the trait of interest in the population. Finally, a dense single-nucleotide polymorphism genotyping array (Illumina 318K) was used to search for copy number variations (CNVs) in the associated regions. In the families with extreme phenotype scores, we found significant evidence of linkage for conscientiousness to 20p13 (rs1434789, log of odds (LOD)5.86) and suggestive evidence of linkage (LOD 2.8) for neuroticism to 19q, 21q and 22q, extraversion to 1p, 1q, 9p and12q, openness to 12q and 19q, and agreeableness to 2p, 6q, 17q and 21q. Further analysis determined haplotypes in 21q22 for neuroticism (P-values0.009, 0.007), in 17q24 for agreeableness (marginal P-value0.018) and in 20p13 for conscientiousness (marginal P-values0.058, 0.038) segregating in families with large contributions to the LOD scores. No evidence for CNVs in any of the associated regions was found. Our findings imply that there may be genes with relatively large effects involved in personality traits, which may be identified with next-generation sequencing techniques. © 2012 Macmillan Publishers Limited All rights reserved.


Cornel M.C.,VU University Amsterdam | Cornel M.C.,Center for Medical Systems Biology | Cornel M.C.,Center for Society and the Life science | Van El C.G.,VU University Amsterdam | And 4 more authors.
Journal of Community Genetics | Year: 2014

Genetics and genomics have developed fast in the last decade, but have not revolutionizedmedicine, as some had expected. While translation of research findings to public health applications is lagging behind, direct-to-consumer (DTC) offers of genetic testing have become available, both for monogenic and severe genetic disorders and for genetic variants possibly associated with common complex diseases (susceptibility variants). The European Society of Human Genetics is concerned about the way in which commercial companies are currently introducing genetic tests into the market outside of the scope of the traditional health-care system. There is a sort of a paradox between the lagging implementation in health care of the few genetic tests with proven clinical utility, on the one hand, and the speedy DTC offer of tests, with or without clinical utility. To translate research findings into appropriate clinical applications, assessment of the clinical validity and utility is needed. Many of the parameters needed in assessment frameworks are not available yet. Clinically relevant associations between genetic variants and disease risks have been established, e.g., in oncogenetics and cardiogenetics, and can be used to reflect on the possibilities and obstacles in using the new genetics in public health. In the absence of sufficient information on clinical validity and clinical utility, introduction of genetic tests in common complex disorders is often premature. Priority should be given to settings where clinical utility is proven or likely, to gain additional information concerning diagnosis, prognosis, and disease management. Monitoring and evaluation are essential. © Springer-Verlag 2012.


van Iterson M.,Leiden University | van Iterson M.,Netherlands Bioinformatics Center | Boer J.M.,Leiden University | Boer J.M.,Netherlands Bioinformatics Center | And 4 more authors.
BMC Bioinformatics | Year: 2010

Background: In high-dimensional data analysis such as differential gene expression analysis, people often use filtering methods like fold-change or variance filters in an attempt to reduce the multiple testing penalty and improve power. However, filtering may introduce a bias on the multiple testing correction. The precise amount of bias depends on many quantities, such as fraction of probes filtered out, filter statistic and test statistic used.Results: We show that a biased multiple testing correction results if non-differentially expressed probes are not filtered out with equal probability from the entire range of p-values. We illustrate our results using both a simulation study and an experimental dataset, where the FDR is shown to be biased mostly by filters that are associated with the hypothesis being tested, such as the fold change. Filters that induce little bias on the FDR yield less additional power of detecting differentially expressed genes. Finally, we propose a statistical test that can be used in practice to determine whether any chosen filter introduces bias on the FDR estimate used, given a general experimental setup.Conclusions: Filtering out of probes must be used with care as it may bias the multiple testing correction. Researchers can use our test for FDR bias to guide their choice of filter and amount of filtering in practice. © 2010 van Iterson et al; licensee BioMed Central Ltd.


Rigter T.,VU University Amsterdam | van Aart C.J.A.,VU University Amsterdam | Elting M.W.,VU University Amsterdam | Waisfisz Q.,VU University Amsterdam | And 4 more authors.
Clinical Genetics | Year: 2014

Next-generation sequencing is increasingly being chosen as a diagnostic tool for cases of expected genetic, but unresolved origin. The consequential increased need for decisions on disclosure of unsolicited findings poses a challenge for the informed consent procedure. This study explored the first experiences with, and needs for, the informed consent procedure in diagnostic exome sequencing, with the stakeholders involved. Semi-structured interviews were conducted with 11 professional experts and one professional gave a written response. Furthermore, the counseling process was observed in three cases where exome sequencing was offered, followed by interviews with the patient (representative) and the genetic counselor. The respondents not only preferred an opt-out for unsolicited findings but also identified many challenges and therefore more experiences with exome sequencing was considered needed. Context-dependent decision-making was observed and an Advisory Board for unsolicited findings was considered helpful while doubts were raised about the feasibility and the possibility of undermining patients' autonomy. Finally, respondents brought up the complexity of information provision, and division of responsibilities between clinicians and the lab. These challenges and needs, raised by stakeholders involved, provide more insight in the next steps needed for an optimal informed consent procedure for exome sequencing in diagnostics. © 2013 The Authors. Clinical Genetics published by JohnWiley & Sons A/S. Published by John Wiley & Sons Ltd.


Vermeulen E.,VU University Amsterdam | Vermeulen E.,Netherlands Cancer Institute | Henneman L.,VU University Amsterdam | Van El C.G.,VU University Amsterdam | And 3 more authors.
European Journal of Public Health | Year: 2013

Background: Genetic testing and family history assessment can be used as an aid in the prevention of common chronic diseases. The aim of this study was to determine public attitudes and interests towards offering genetic testing and family history-based risk assessment for common chronic disease prevention. Methods: Cross-sectional questionnaire survey of a consumer panel representative for the Dutch population. The questionnaire was sent to 1399 panel members, aged â18 years. Results: The response was 70% (978/1399). About half of the respondents expressed an interest in genetic testing to prevent specific diseases (cancer, cardiovascular disease, diabetes or dementia), with lower-educated respondents showing more interest than higher-educated respondents. Few respondents (24%) agreed that people should be preventively tested for all kinds of diseases. According to the respondents, genetic testing should be performed in the hospital (66%) and be directed to curable (57%) or preventable diseases (69%). Half of the respondents believed that family history assessment could help prevent disease, but only 21% thought it should be offered to everyone, as this could cause people to be worried. A minority (12%) reported that their family history had been assessed, whereas 59% did not have it assessed and did not think this would be necessary. Respondents have differentiated interests in preventive genomics, which varies depending on sex, age and level of education. Conclusions: Members of the public are interested in genetic testing for preventable and curable diseases, but they are ambivalent about family history risk assessment to prevent disease. © 2013 © The Author 2013. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.

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