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Article ; Online: Metasubtract: an R-package to analytically produce leave-one-out meta-analysis GWAS summary statistics.

Nolte, Ilja M

2020 Volume 36, Issue 16, Page(s) 4521–4522

Abstract: Summary: statistics from a meta-analysis of genome-wide association studies (meta-GWAS) can be used for many follow-up analyses. One valuable application is the creation of polygenic scores. However, if polygenic scores are calculated in a validation ... ...

Abstract	Summary: statistics from a meta-analysis of genome-wide association studies (meta-GWAS) can be used for many follow-up analyses. One valuable application is the creation of polygenic scores. However, if polygenic scores are calculated in a validation cohort that was part of the meta-GWAS consortium, this cohort is not independent and analyses will therefore yield inflated results. The R package 'MetaSubtract' was developed to subtract the results of the validation cohort from meta-GWAS summary statistics analytically. The statistical formulas for a meta-analysis were inverted to compute corrected summary statistics of a meta-GWAS leaving one (or more) cohort(s) out. These formulas have been implemented in MetaSubtract for different meta-analyses methods (fixed effects inverse variance or square root sample size weighted z-score) accounting for no, single or double genomic control correction. Results obtained by MetaSubtract correlate very well to those calculated using the traditional way, i.e. by performing a meta-analysis leaving out the validation cohort. In conclusion, MetaSubtract allows researchers to compute meta-GWAS summary statistics that are independent of the GWAS results of the validation cohort without requiring access to the cohort level GWAS results of the corresponding meta-GWAS consortium. Availability and implementation: https://cran.r-project.org/web/packages/MetaSubtract. Supplementary information: Supplementary data are available at Bioinformatics online.
MeSH term(s)	Genome-Wide Association Study ; Genotype ; Humans ; Multifactorial Inheritance ; Polymorphism, Single Nucleotide ; Sample Size ; Software
Language	English
Publishing date	2020-05-07
Publishing country	England
Document type	Journal Article ; Meta-Analysis
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btaa570
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Article ; Online: Genetic confounding in bullying research: Causal claims revisited.

Vrijen, Charlotte / Nolte, Ilja M / Oldehinkel, Albertine J / Veenstra, René / Kretschmer, Tina

Development and psychopathology

2023 , Page(s) 1–12

Abstract: Bullying research has shown repeatedly that victims of bullying have an increased risk for later internalizing problems and bullies have an increased risk for later externalizing problems. Bullying involvement is often, either explicitly or implicitly, ... ...

Abstract	Bullying research has shown repeatedly that victims of bullying have an increased risk for later internalizing problems and bullies have an increased risk for later externalizing problems. Bullying involvement is often, either explicitly or implicitly, presented as part of a causal mechanism for maladjustment. However, genetic vulnerability may confound the reported associations. This study examined to what extent genetic vulnerability can account for the reported associations between bullying involvement (age 11-14) and later internalizing and externalizing problems (age 16), using data from the TRacking Adolescents' Individual Lives Survey (
Language	English
Publishing date	2023-04-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	1036173-x
ISSN	1469-2198 ; 0954-5794
ISSN (online)	1469-2198
ISSN	0954-5794
DOI	10.1017/S0954579423000445
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Article ; Online: Distal-to-proximal etiologically relevant variables associated with the general (p) and specific factors of psychopathology.

Ormel, Jonah / Vos, Melissa / Laceulle, Odilia M / Vrijen, Charlotte / van der Laan, Camiel M / Nolte, Ilja M / Hartman, Catharina A

Journal of child psychology and psychiatry, and allied disciplines

2024

Abstract: Background: The general factor of psychopathology, often denoted as p, captures the common variance among a broad range of psychiatric symptoms. Specific factors are co-modeled based on subsets of closely related symptoms. This paper investigated the ... ...

Abstract	Background: The general factor of psychopathology, often denoted as p, captures the common variance among a broad range of psychiatric symptoms. Specific factors are co-modeled based on subsets of closely related symptoms. This paper investigated the extent to which wide-ranging genetic, personal, and environmental etiologically relevant variables are associated with p and specific psychopathology factors. Methods: Using data from four waves (ages 11-19) of TRAILS, we modeled a bifactor model of p and four specific factors [internalizing, externalizing, ADHD, Autism Spectrum Disorder (ASD)]. Next, we examined the associations of 19 etiologically relevant variables with these psychology factors using path models that organized the variables according to the distal-to-proximal risk principle. Results: Collectively, the etiologically relevant factors, including temperament traits, accounted for 55% of p's variance, 46% in ADHD, 35% in externalizing, 19% in internalizing, and 7% in ASD. The low 7% is due to insufficient unique variance in ASD indicators that load more strongly on p. Excluding temperament, variables accounted for 29% variance in p, 9% ADHD, 14% EXT, 7% INT, and 4% ASD. Most etiologically relevant factors were generic, predicting p. In addition, we identified effects on specific factors in addition to effects on p (e.g., parental SES, executive functioning); only effects on specific factors (e.g., parental rejection); opposite effects on different factors [e.g., diurnal cortisol (high INT but low EXT, p); developmental delay (high ASD and p but low EXT)]. Frustration, family functioning, parental psychopathology, executive functioning, and fearfulness had strong effects on p. Conclusions: (1) Strong generic effects on p suggest that etiologically relevant factors and psychopathology tend to cluster in persons. (2) While many factors predict p, additional as well as opposite effects on specific factors indicate the relevance of specific psychopathology factors in understanding mental disorder. (3) High frustration, neurodevelopmental problems, and a disadvantaged family environment primarily characterize p.
Language	English
Publishing date	2024-03-19
Publishing country	England
Document type	Journal Article
ZDB-ID	218136-8
ISSN	1469-7610 ; 0021-9630 ; 0373-8086
ISSN (online)	1469-7610
ISSN	0021-9630 ; 0373-8086
DOI	10.1111/jcpp.13979
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Article: A Principal Component Informed Approach to Address Polygenic Risk Score Transferability Across European Cohorts.

Pärna, Katri / Nolte, Ilja M / Snieder, Harold / Fischer, Krista / Marnetto, Davide / Pagani, Luca

Frontiers in genetics

2022 Volume 13, Page(s) 899523

Abstract: One important confounder in genome-wide association studies (GWASs) is population genetic structure, which may generate spurious associations if not properly accounted for. This may ultimately result in a biased polygenic risk score (PRS) prediction, ... ...

Abstract	One important confounder in genome-wide association studies (GWASs) is population genetic structure, which may generate spurious associations if not properly accounted for. This may ultimately result in a biased polygenic risk score (PRS) prediction, especially when applied to another population. To explore this matter, we focused on principal component analysis (PCA) and asked whether a population genetics informed strategy focused on PCs derived from an external reference population helps in mitigating this PRS transferability issue. Throughout the study, we used two complex model traits, height and body mass index, and samples from UK and Estonian Biobanks. We aimed to investigate 1) whether using a reference population (1000G) for computation of the PCs adjusted for in the discovery cohort improves the resulting PRS performance in a target set from another population and 2) whether adjusting the validation model for PCs is required at all. Our results showed that any other set of PCs performed worse than the one computed on samples from the same population as the discovery dataset. Furthermore, we show that PC correction in GWAS cannot prevent residual population structure information in the PRS, also for non-structured traits. Therefore, we confirm the utility of PC correction in the validation model when the investigated trait shows an actual correlation with population genetic structure, to account for the residual confounding effect when evaluating the predictive value of PRS.
Language	English
Publishing date	2022-07-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2022.899523
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Article ; Online: Development and validation of a questionnaire-based myopia proxy in adults: the LifeLines Cohort Study.

Asefa, Nigus G / Neustaeter, Anna / Vehof, Jelle / Nolte, Ilja M / Snieder, Harold / Jansonius, Nomdo M

The British journal of ophthalmology

2022 Volume 107, Issue 7, Page(s) 1035–1042

Abstract: Aims: To build a questionnaire-based myopia proxy and to validate the proxy by confirming its association with educational attainment and a Polygenic Risk Score (PRS) for myopia.: Methods: Data were collected between 2014 and 2017 from 88 646 Dutch ... ...

Abstract	Aims: To build a questionnaire-based myopia proxy and to validate the proxy by confirming its association with educational attainment and a Polygenic Risk Score (PRS) for myopia. Methods: Data were collected between 2014 and 2017 from 88 646 Dutch adults from the LifeLines Cohort. First, we performed principal component analysis (PCA) to responses of five refraction-status questions. Second, we measured the refractive state in a subset of LifeLines participants (n=326) and performed logistic regression using myopia (mean spherical equivalent <-0.5 D) as a dependent variable and the principal components (PCs) as independent variables. We identified specificity, sensitivity and the classification threshold. Third, the classification equation was applied to the remaining LifeLines participants. The value of the proxy was then explored by calculating its association with educational attainment and a PRS of myopia. Results: A total of 77 096 participants (58.1% women) were eligible for the PCA. The first two PCs had a specificity of 91.9% (95% CI 87.8% to 95.4%) and a sensitivity of 90.4% (95% CI 84.3% to 96.4%) for myopia. The area under the receiver operating characteristic curve was 95.0% (95% CI 92.2% to 97.8%). The age-standardised prevalence of proxy-inferred myopia was 33.8% (95% CI 33.4% to 34.3%). Compared with low education level, the ORs of proxy-inferred myopia were 1.66 (95% CI 1.58 to 1.74, p=5.94×10 Conclusion: Self-administered refractive error-related questions could be used as an effective tool to capture proxy-inferred myopic cases in a population-based setting.
MeSH term(s)	Humans ; Adult ; Female ; Male ; Cohort Studies ; Myopia/diagnosis ; Myopia/epidemiology ; Refractive Errors ; Refraction, Ocular ; Surveys and Questionnaires ; Prevalence
Language	English
Publishing date	2022-03-10
Publishing country	England
Document type	Journal Article
ZDB-ID	80078-8
ISSN	1468-2079 ; 0007-1161
ISSN (online)	1468-2079
ISSN	0007-1161
DOI	10.1136/bjophthalmol-2021-319166
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Article ; Online: Familial co-aggregation and shared genetics of cardiometabolic disorders and traits: data from the multi-generational Lifelines Cohort Study.

Triatin, Rima D / Chen, Zekai / Ani, Alireza / Wang, Rujia / Hartman, Catharina A / Nolte, Ilja M / Thio, Chris H L / Snieder, Harold

Cardiovascular diabetology

2023 Volume 22, Issue 1, Page(s) 282

Abstract: Background: It is unclear to what extent genetics explain the familial clustering and the co-occurrence of distinct cardiometabolic disorders in the general population. We therefore aimed to quantify the familial (co-)aggregation of various ... ...

Abstract	Background: It is unclear to what extent genetics explain the familial clustering and the co-occurrence of distinct cardiometabolic disorders in the general population. We therefore aimed to quantify the familial (co-)aggregation of various cardiometabolic disorders and to estimate the heritability of cardiometabolic traits and their genetic correlations using the large, multi-generational Lifelines Cohort Study. Methods: We used baseline data of 162,416 participants from Lifelines. Cardiometabolic disorders including type 2 diabetes (T2D), cardiovascular diseases, hypertension, obesity, hypercholesterolemia, and metabolic syndrome (MetS), were defined in adult participants. Fifteen additional cardiometabolic traits indexing obesity, blood pressure, inflammation, glucose regulation, and lipid levels were measured in all included participants. Recurrence risk ratios (λ Results: Individuals with a first-degree relative with a cardiometabolic disorder had a higher risk of the same disorder, ranging from λ Conclusions: There is positive familial (co-)aggregation of cardiometabolic disorder, moderate heritability of intermediate traits, and moderate genetic correlations between traits. These results indicate that shared genetics and common genetic architecture contribute to cardiometabolic disease.
MeSH term(s)	Adult ; Humans ; Diabetes Mellitus, Type 2/diagnosis ; Diabetes Mellitus, Type 2/epidemiology ; Diabetes Mellitus, Type 2/genetics ; Cohort Studies ; Metabolic Syndrome/diagnosis ; Metabolic Syndrome/epidemiology ; Metabolic Syndrome/genetics ; Obesity/diagnosis ; Obesity/epidemiology ; Obesity/genetics ; Cardiovascular Diseases/diagnosis ; Cardiovascular Diseases/epidemiology ; Cardiovascular Diseases/genetics ; Hypertension
Language	English
Publishing date	2023-10-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2093769-6
ISSN	1475-2840 ; 1475-2840
ISSN (online)	1475-2840
ISSN	1475-2840
DOI	10.1186/s12933-023-02017-w
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Article ; Online: Clinical longevity of extensive direct resin composite restorations after amalgam replacement with a mean follow-up of 15 years.

Hofsteenge, Jelte W / Scholtanus, Johannes D / Özcan, Mutlu / Nolte, Ilja M / Cune, Marco S / Gresnigt, Marco M M

Journal of dentistry

2023 Volume 130, Page(s) 104409

Abstract: Objectives: The aim of this retrospective clinical study was to determine the survival of extensive direct resin composite restorations after amalgam replacement on vital molars and premolars after a mean observation period of 15 years.: Methods: ... ...

Abstract	Objectives: The aim of this retrospective clinical study was to determine the survival of extensive direct resin composite restorations after amalgam replacement on vital molars and premolars after a mean observation period of 15 years. Methods: Between January 2007 and September 2013, a total of 117 extensive cusp replacing direct resin composite restorations were placed in 88 patients in a general dental practice. These were indicated for replacement of existing amalgam restorations. Tooth vitality, the absence of at least one cusp in premolars, and at least two cusps in molars were considered for inclusion. The long-term follow-up of the restorations, re-evaluated after up to 17 years using the original evaluation criteria is reported. Results: 81 of 88 patients (92.1%) and 106 of 117 restorations (90.6%) were available for follow-up. The cumulative success rate was 62.0% (95% CI: 47.3-76.2, AFR 2.79%) after a mean observation time of 163.4 months, the cumulative survival rate was 74.7% (95% CI: 59.8-89.6%, AFR: 1.70%) after a mean observation time of 179.1 months. The number of cusps replaced in premolars had a statistically significant influence on the success and survival rate of the restorations (HR of respectively, 2.974 and 3.175, p = <0.0005). Premolars with two cusps replaced had 297% more chance of failure than premolars with one cusp replaced. Conclusions: Extensive direct resin composite restorations placed after amalgam replacement showed good survival after a mean observation period of 15 years. The number of cusps involved had a statistically significant influence on the longevity of the restorations in premolars. Clinical significance: With good survival and low annual failure rates, direct resin composite restorations are a suitable treatment for repairing extensive defects in posterior teeth involving multiple cusps and surfaces, provided that they are placed by a dentist who has long experience and is skilled in the placement of direct composite materials.
MeSH term(s)	Humans ; Dental Restoration, Permanent ; Retrospective Studies ; Follow-Up Studies ; Composite Resins/therapeutic use ; Longevity ; Dental Amalgam/therapeutic use ; Dental Restoration Failure
Chemical Substances	Composite Resins ; Dental Amalgam (8049-85-2)
Language	English
Publishing date	2023-01-06
Publishing country	England
Document type	Journal Article
ZDB-ID	186068-9
ISSN	1879-176X ; 0300-5712
ISSN (online)	1879-176X
ISSN	0300-5712
DOI	10.1016/j.jdent.2023.104409
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Article ; Online: Elevated serum TARC levels precede classic Hodgkin lymphoma diagnosis by several years.

Diepstra, Arjan / Nolte, Ilja M / van den Berg, Anke / Magpantay, Larry I / Martínez-Maza, Otoniel / Levin, Lynn I

Blood

2023 Volume 142, Issue 22, Page(s) 1928–1931

Abstract: Tumor cells in classic Hodgkin lymphoma produce high quantities of the thymus- and activation-related chemokine (TARC). We measured TARC levels in prediagnostic serum samples and found strikingly increased values in the vast majority of patients, as ... ...

Abstract	Tumor cells in classic Hodgkin lymphoma produce high quantities of the thymus- and activation-related chemokine (TARC). We measured TARC levels in prediagnostic serum samples and found strikingly increased values in the vast majority of patients, as early as 6 years before diagnosis.
MeSH term(s)	Humans ; Hodgkin Disease/pathology ; Chemokine CCL17 ; Chemokines
Chemical Substances	Chemokine CCL17 ; Chemokines
Language	English
Publishing date	2023-09-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2023020959
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Article ; Online: A genome-wide association meta-analysis implicates Hedgehog and Notch signaling in Dupuytren's disease.

Riesmeijer, Sophie A / Kamali, Zoha / Ng, Michael / Drichel, Dmitriy / Piersma, Bram / Becker, Kerstin / Layton, Thomas B / Nanchahal, Jagdeep / Nothnagel, Michael / Vaez, Ahmad / Hennies, Hans Christian / Werker, Paul M N / Furniss, Dominic / Nolte, Ilja M

Nature communications

2024 Volume 15, Issue 1, Page(s) 199

Abstract: Dupuytren's disease (DD) is a highly heritable fibrotic disorder of the hand with incompletely understood etiology. A number of genetic loci, including Wnt signaling members, have been previously identified. Our overall aim was to identify novel genetic ... ...

Abstract	Dupuytren's disease (DD) is a highly heritable fibrotic disorder of the hand with incompletely understood etiology. A number of genetic loci, including Wnt signaling members, have been previously identified. Our overall aim was to identify novel genetic loci, to prioritize genes within the loci for functional studies, and to assess genetic correlation with associated disorders. We performed a meta-analysis of six DD genome-wide association studies from three European countries and extensive bioinformatic follow-up analyses. Leveraging 11,320 cases and 47,023 controls, we identified 85 genome-wide significant single nucleotide polymorphisms in 56 loci, of which 11 were novel, explaining 13.3-38.1% of disease variance. Gene prioritization implicated the Hedgehog and Notch signaling pathways. We also identified a significant genetic correlation with frozen shoulder. The pathways identified highlight the potential for new therapeutic targets and provide a basis for additional mechanistic studies for a common disorder that can severely impact hand function.
MeSH term(s)	Humans ; Animals ; Dupuytren Contracture/genetics ; Dupuytren Contracture/metabolism ; Genome-Wide Association Study ; Hedgehogs/genetics ; Wnt Signaling Pathway ; Genetic Loci ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease
Language	English
Publishing date	2024-01-03
Publishing country	England
Document type	Meta-Analysis ; Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-44451-0
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Article ; Online: Ethnic differences in prevalence of Dupuytren disease can partly be explained by known genetic risk variants.

Riesmeijer, Sophie A / Werker, Paul M N / Nolte, Ilja M

European journal of human genetics : EJHG

2019 Volume 27, Issue 12, Page(s) 1876–1884

Abstract: Dupuytren disease (DD), a fibroproliferative disorder of the palmar fascia that causes flexion contractures in the fingers, is prevalent in people of North-Western European descent and less so in other ethnicities. DD is a complex disorder, influenced by ...

Abstract	Dupuytren disease (DD), a fibroproliferative disorder of the palmar fascia that causes flexion contractures in the fingers, is prevalent in people of North-Western European descent and less so in other ethnicities. DD is a complex disorder, influenced by genetic risk variants. We aimed to study if the marked differences in prevalences in DD between ethnic (sub)groups could be explained by differences in allele frequencies of the 26 known genetic risk variants of DD. Therefore, genetic risk scores (GRS) composed of the 26 DD risk variants were calculated for the 26 populations from the 1000 Genomes database and correlated to observed DD prevalences from literature. For comparison, GRSs were generated for 10,000 sets of 26 random SNPs and also correlated to the observed DD prevalences to determine the significance of the observed correlation. To determine whether differences in allele frequencies between ethnicities were caused by natural selection, fixation indices (Fst) were calculated from the 26 SNPs and from the sets of 26 random SNPs for comparison. Observed prevalences could be determined from literature for 10 populations. Their correlation with the GRS composed of DD SNPs proved to be 0.60 (p = 0.0003). The Fsts between British and other populations were low for European, ad mixed American, and South-Asian populations, and moderate for East-Asians. African populations were significantly different from expected values determined from the random sets. In conclusion, the 26 known genetic risk variants associated with DD explain for a substantial part (R
MeSH term(s)	Adult ; Aged ; Asian People/genetics ; Black People/genetics ; Dupuytren Contracture/epidemiology ; Dupuytren Contracture/genetics ; Dupuytren Contracture/pathology ; Ethnicity/genetics ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genotype ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide/genetics ; Risk Factors ; Selection, Genetic/genetics ; White People/genetics
Language	English
Publishing date	2019-07-30
Publishing country	England
Document type	Journal Article
ZDB-ID	1141470-4
ISSN	1476-5438 ; 1018-4813
ISSN (online)	1476-5438
ISSN	1018-4813
DOI	10.1038/s41431-019-0483-5
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