Objectives: Erosive hand osteoarthritis (EHOA) is a severe subset of hand osteoarthritis (OA). It is unclear if EHOA is genetically different from other forms of OA. Sequence variants at ten loci... Show moreObjectives: Erosive hand osteoarthritis (EHOA) is a severe subset of hand osteoarthritis (OA). It is unclear if EHOA is genetically different from other forms of OA. Sequence variants at ten loci have been associated with hand OA but none with EHOA. Methods: We performed meta-analysis of EHOA in 1484 cases and 550 680 controls, from 5 populations. To identify causal genes, we performed eQTL and plasma pQTL analyses, and developed one zebrafish mutant. We analysed associations of variants with other traits and estimated shared genetics between EHOA and other traits. Results: Four common sequence variants associated with EHOA, all with relatively high effect. Rs17013495 (SPP1/MEPE, OR=1.40, p=8.4x10(-14)) and rs11243284 (6p24.3, OR=1.35, p=4.2x10(-11)) have not been associated with OA, whereas rs11631127 (ALDH1A2, OR=1.46, p=7.1x10(-18)), and rs1800801 (MGP, OR=1.37, p=3.6x10(-13)) have previously been associated with hand OA. The association of rs1800801 (MGP) was consistent with a recessive mode of inheritance in contrast to its additive association with hand OA (OR homozygotes vs non-carriers=2.01, 95% CI 1.71 to 2.37). All four variants associated nominally with finger OA, although with substantially lower effect. We found shared genetic components between EHOA and other OA measures, grip strength, urate levels and gout, but not rheumatoid arthritis. We identified ALDH1A2, MGP and BMP6 as causal genes for EHOA, with loss-of-function Bmp6 zebrafish mutants displaying EHOA-like phenotypes. Conclusions: We report on significant genetic associations with EHOA. The results support the view of EHOA as a form of severe hand OA and partly separate it from OA in larger joints. Show less
Lakeman, I.M.M.; Rodriguez Girondo, M.D.M.; Lee, A.; Celosse, N.; Braspenning, M.E.; Engelen, K. van; ... ; Devilee, P. 2022
Background: Common low-risk variants are presently not used to guide clinical management of familial breast cancer (BC). We explored the additive impact of a 313-variant-based Polygenic Risk Score ... Show moreBackground: Common low-risk variants are presently not used to guide clinical management of familial breast cancer (BC). We explored the additive impact of a 313-variant-based Polygenic Risk Score (PRS313) relative to standard gene testing in non-BRCA1/2 Dutch BC families. Methods: We included 3918 BC cases from 3492 Dutch non-BRCA1/2 BC families and 3474 Dutch population controls. The association of the standardised PRS313 with BC was estimated using a logistic regression model, adjusted for pedigree-based family history. Family history of the controls was imputed for this analysis. SEs were corrected to account for relatedness of individuals. Using the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) V.5 model, lifetime risks were retrospectively calculated with and without individual PRS313. For 2586 cases and 2584 controls, the carrier status of pathogenic variants (PVs) in ATM, CHEK2 and PALB2 was known. Results: The family history-adjusted PRS313 was significantly associated with BC (per SD OR=1.97, 95% CI 1.84 to 2.11). Including the PRS313 in BOADICEA family-based risk prediction would have changed screening recommendations in up to 27%, 36% and 34% of cases according to BC screening guidelines from the USA, UK and the Netherlands (National Comprehensive Cancer Network, National Institute for Health and Care Excellence, and Netherlands Comprehensive Cancer Organisation), respectively. For the population controls, without information on family history, this was up to 39%, 44% and 58%, respectively. Among carriers of PVs in known moderate BC susceptibility genes, the PRS313 had the largest impact for CHEK2 and ATM. Conclusions: Our results support the application of the PRS313 in risk prediction for genetically uninformative BC families and families with a PV in moderate BC risk genes. Show less
Bredart, A.; Pauw, A. de; Anota, A.; Tuchler, A.; Dick, J.; Muller, A.; ... ; Dolbeault, S. 2021
Objectives: Comprehensive breast cancer (BC) risk models integrating effects of genetic (GRF) and non-genetic risk factors (NGRF) may refine BC prevention recommendations. We explored the perceived... Show moreObjectives: Comprehensive breast cancer (BC) risk models integrating effects of genetic (GRF) and non-genetic risk factors (NGRF) may refine BC prevention recommendations. We explored the perceived information received on BC risk factors, and related characteristics, in female relatives of women with a BRCA1/2 or PALB2 pathogenic variant, undergoing BC risk assessment using the CanRisk(C) prediction tool.Methods: Of 200 consecutive cancer-free women approached after the initial genetic consultation, 161 (80.5%) filled in questionnaires on their perception of information received and wished further information on BC risk factors (e.g., being a carrier of a moderate risk altered gene, personal genetic profile, lifestyles). Multilevel multivariate linear models were performed accounting for the clinician who met the counselee and exploring the effect of counselees' socio-demographic, familial and psychological characteristics on the perceived extent of information received.Results: Perceived no/little information received and wish for further information were more frequent for NGRF (>50%) than for GRF, especially high-risk genes (<20%). Perceived amount of information received and desire for further information were inversely correlated (p=<0.0001). Higher education level related to lower perceived levels of information received on GRF. Younger counselees' age (beta = 0.13, p = 0.02) and less frequent engagement coping (e.g., inclination to solicit information) (beta = 0.24, p = 0.02) related to lower perceived information received about NGRF. Other assessed counselees' features were not found to be associated to GRF and NGRF information perception.Conclusions: Awareness of counselees' perceived lack of information on BC risk factors indicates a need to enhance evidence-based information on BC NGRF especially. (C) 2021 The Authors. Published by Elsevier Ltd. Show less
The major challenge in analysing omic datasets is the strong dependencies which are present between samples and features. Taking into account and modelling the different dependency structures can... Show moreThe major challenge in analysing omic datasets is the strong dependencies which are present between samples and features. Taking into account and modelling the different dependency structures can lead to further improvements of our knowledge of the biological mechanisms. Therefore, improving our ability to predict diseases. This dissertation focuses on the development of new statistical methods designed to take into account the existing structures inside omic datasets by using mixed models, Gaussian graphical models, and machine learning approaches. Show less
Uveal melanoma (UM) is an aggressive intraocular tumor with a high propensity to metastasize. Accurate prognostication is relevant for patient counselling, planning of follow-up and... Show moreUveal melanoma (UM) is an aggressive intraocular tumor with a high propensity to metastasize. Accurate prognostication is relevant for patient counselling, planning of follow-up and stratification of patients in clinical trials. Discoveries of prognostically relevant genetic markers in the last few decades have fuelled the advancement of prognostication in UM considerably. In this thesis, we explored ways of improving genetic prognostication in UM, evaluated the effect of irradiation on chromosome testing, and investigated the association of DNA repair genes and epigenetic regulators with prognosis. We reveal that chromosome markers of high malignancy such as monosomy 3 and chromosome 8q gain are less often observed in patients who die due to metastases at a late stage. We demonstrate that combining the AJCC staging and chromosome 3 and 8q status results in enhanced risk stratification. We provide evidence that supports the taking of biopsies before radiotherapy is applied since chromosome testing seems to fail more often in irradiated tumors. Furthermore, we show that evaluating the role of DNA repair and epigenetics in uveal melanoma can help in unraveling the biology of uveal melanoma and identifying new markers for prognostication. Show less
Harland, M.; Petljak, M.; Robles-Espinoza, C.D.; Ding, Z.H.; Gruis, N.A.; Doorn, R. van; ... ; Bishop, D.T. 2016
In this dissertation clinical genetic investigations on migraine, related syndromes and comorbid conditions are described. The first migraine syndrome studied is Familial Hemiplegic Migraine (FHM),... Show moreIn this dissertation clinical genetic investigations on migraine, related syndromes and comorbid conditions are described. The first migraine syndrome studied is Familial Hemiplegic Migraine (FHM), a monogenic migraine variant. The clinical spectrum of FHM1-3 and the relation with closely related diseases such as Alternating hemiplegia of Chilhood, Early Seizures and Cerebral Edema after Trivial Head Trauma, epilepsy and episodic ataxia were investigated. The second monogenic migraine syndrome studied is Retinal Vasculopathy with Cerebral Leukodystrophy (later renamed CHARIOT), where common migraine is part of the clinical spectrum. The identification of TREX1 as the causal gene for RVCL is described. Investigation of the clinical spectrum showed retinal, cerebral and internal organ involvement, without an apparent genotype-phenotype correlation. Endothelial dysfunction of large arteries was shown in RVCL patients and is proposed as a possible disease mechanism. Lastly, migraine patients were identified in a Dutch genetic isolate and the relation with depression and atherosclerosis was assessed. For depression it was shown that shared genetic factors, at least partly, underlie the comorbidity with migraine, in particular migraine with aura. These studies improve our insight in genetic factors and pathofysiological mechanisms involved in migraine, which may ultimately contribute to better treatment options for migraine patients Show less
Adducted thumbs are an uncommon congenital malformation. It can be an important clinical clue in genetic syndromes, e.g. the L1 syndrome. A retrospective survey was performed including patients... Show moreAdducted thumbs are an uncommon congenital malformation. It can be an important clinical clue in genetic syndromes, e.g. the L1 syndrome. A retrospective survey was performed including patients with adducted thumbs referred to the Department of Clinical Genetics between 1985 and 2011 by perinatologists, (child) neurologists or paediatricians, in order to evaluate current knowledge on the genetic etiology of adducted thumbs. Twenty-five patients were included in this survey. Additional features were observed in 88% (22/25). In 25% (4/16) of the patients with adducted thumbs and congenital hydrocephalus L1CAM gene mutations were identified. One patient had a mosaic 5p13 duplication. Recommendations are made concerning the evaluation and genetic workup of patients with adducted thumbs. Show less
Rover, M. de; Brown, S.B.R.E.; Boot, N.; Hajcak, G.; Noorden, M.S. van; Wee, N.J.A. van der; Nieuwenhuis, S. 2012
The research in this thesis was aimed at identifying and characterizing novel migraine gene mutations and pathways. Several FHM and non-FHM genes were investigated in patients with monogenic... Show moreThe research in this thesis was aimed at identifying and characterizing novel migraine gene mutations and pathways. Several FHM and non-FHM genes were investigated in patients with monogenic familial hemiplegic migraine or other monogenic disorders in which migraine can be prevalent. Functional consequences of these mutations and the clinical phenotypes associated with them were investigated. Common migraine with a complex genetic background was studied using a genome-wide association analysis in an isolated population and with a meta-analysis study. Furthermore, FHM1 mice were used to study expression profiles in brain tissues that are relevant for the induction of cortical spreading depression ___ underlying the migraine aura - (i.e., the occipital cortex) and cerebellar ataxia (i.e., the cerebellum). These studies will further our insight in the molecular pathophysiology of migraine. Show less
