ORCID Profile
0000-0003-0292-2351
Current Organisations
Statens Serum Institut
,
Delft University of Technology
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Publisher: Cold Spring Harbor Laboratory
Date: 20-11-2020
DOI: 10.1101/2020.11.18.20233916
Abstract: Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental, and developmental factors. While usually benign, in a minority of cases, febrile seizures precede later development of epilepsy. Here, we conducted a genome-wide association study of febrile seizures with 7,635 cases and 93,966 controls identifying and replicating seven new loci, all with P 5 × 10 −10 . Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10 , and four other loci harbored genes ( BSN, ERC2, GABRG2, HERC1 ) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. GABRG2 is a well-established epilepsy gene comprising variants associated with febrile seizures, and overall we found positive genetic correlations with epilepsies ( r g = 0.39, P = 1.68 × 10 −4 ). Finally, a polygenic risk score based on all genome-wide significant loci was associated within patients with number of hospital admissions with febrile seizures and age at first admission, suggesting potential clinical utility of improved genetic understanding of febrile seizure genesis.
Publisher: Springer Science and Business Media LLC
Date: 07-10-2016
Publisher: Elsevier BV
Date: 06-2018
Publisher: Springer Science and Business Media LLC
Date: 26-11-2018
Publisher: Springer Science and Business Media LLC
Date: 24-11-2020
Publisher: Springer Science and Business Media LLC
Date: 07-03-2018
DOI: 10.1038/S41467-017-02769-6
Abstract: Genomic prediction has the potential to contribute to precision medicine. However, to date, the utility of such predictors is limited due to low accuracy for most traits. Here theory and simulation study are used to demonstrate that widespread pleiotropy among phenotypes can be utilised to improve genomic risk prediction. We show how a genetic predictor can be created as a weighted index that combines published genome-wide association study (GWAS) summary statistics across many different traits. We apply this framework to predict risk of schizophrenia and bipolar disorder in the Psychiatric Genomics consortium data, finding substantial heterogeneity in prediction accuracy increases across cohorts. For six additional phenotypes in the UK Biobank data, we find increases in prediction accuracy ranging from 0.7% for height to 47% for type 2 diabetes, when using a multi-trait predictor that combines published summary statistics from multiple traits, as compared to a predictor based only on one trait.
Publisher: Springer Science and Business Media LLC
Date: 25-03-2019
Publisher: Elsevier BV
Date: 11-2020
Publisher: Elsevier BV
Date: 12-2019
Publisher: Elsevier BV
Date: 06-2018
Publisher: Springer Science and Business Media LLC
Date: 25-11-2020
DOI: 10.1038/S41467-020-19742-5
Abstract: Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10 −8 , odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10 −8 , OR = 1.7 rs143445068, MAF = 0.8%, P = 5.2 × 10 −9 , OR = 3.4 rs183453668, MAF = 0.5%, P = 2.8 × 10 −8 , OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.
Publisher: Springer Science and Business Media LLC
Date: 08-10-2019
DOI: 10.1038/S41467-019-12576-W
Abstract: The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5–20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson’s disease gene involved in dopamine regulation, PARK2 , is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.
Publisher: Springer Science and Business Media LLC
Date: 06-09-2019
DOI: 10.1038/S41380-019-0463-8
Abstract: Based on the discovery by the Resilience Project (Chen R. et al. Nat Biotechnol 34:531–538, 2016) of rare variants that confer resistance to Mendelian disease, and protective alleles for some complex diseases, we posited the existence of genetic variants that promote resilience to highly heritable polygenic disorders1,0 such as schizophrenia. Resilience has been traditionally viewed as a psychological construct, although our use of the term resilience refers to a different construct that directly relates to the Resilience Project, namely: heritable variation that promotes resistance to disease by reducing the penetrance of risk loci, wherein resilience and risk loci operate orthogonal to one another. In this study, we established a procedure to identify unaffected in iduals with relatively high polygenic risk for schizophrenia, and contrasted them with risk-matched schizophrenia cases to generate the first known “polygenic resilience score” that represents the additive contributions to SZ resistance by variants that are distinct from risk loci. The resilience score was derived from data compiled by the Psychiatric Genomics Consortium, and replicated in three independent s les. This work establishes a generalizable framework for finding resilience variants for any complex, heritable disorder.
Publisher: Cold Spring Harbor Laboratory
Date: 22-02-2022
DOI: 10.1101/2022.02.19.22271112
Abstract: The newly found Omicron SARS-CoV-2 variant of concern has rapidly spread worldwide. Omicron carries numerous mutations in key regions and is associated with increased transmissibility and immune escape. The variant has recently been ided into four subvariants with substantial genomic differences, in particular between Omicron BA.1 and BA.2. With the surge of Omicron subvariants BA.1 and BA.2, a large number of reinfections from earlier cases has been observed, raising the question of whether BA.2 specifically can escape the natural immunity acquired shortly after a BA.1 infection. To investigate this, we selected a subset of s les from more than 1,8 million cases of infections in the period from November 22, 2021, until February 11, 2022. Here, in iduals with two positive s les, more than 20 and less than 60 days apart, were selected. From a total of 187 reinfection cases, we identified 47 instances of BA.2 reinfections shortly after a BA.1 infection, mostly in young unvaccinated in iduals with mild disease not resulting in hospitalization or death. In conclusion, we provide evidence that Omicron BA.2 reinfections do occur shortly after BA.1 infections but are rare.
Publisher: Elsevier BV
Date: 06-2018
Publisher: Elsevier BV
Date: 2018
Publisher: Springer Science and Business Media LLC
Date: 25-11-2020
DOI: 10.1038/S41467-020-19733-6
Abstract: Preecl sia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preecl sia in the maternal genome at ZNF831 /20q13 and FTO /16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM /3q26, FGF5 /4q21 and SH2B3 /12q24 also associate with preecl sia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preecl sia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preecl sia.
Publisher: Elsevier BV
Date: 02-2020
Publisher: Springer Science and Business Media LLC
Date: 10-11-2017
DOI: 10.1038/S41598-017-11852-3
Abstract: Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-in idual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables.
No related grants have been discovered for Arjen P. Luijendijk.