Danielle Posthuma

Danielle Posthuma
Vrije Universiteit Amsterdam | VU

PhD

About

534
Publications
172,563
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51,350
Citations
Additional affiliations
November 1996 - present
Vrije Universiteit Amsterdam
Position
  • Professor (Full)

Publications

Publications (534)
Article
Full-text available
Polygenic risk scores (PRSs) can boost risk prediction in late-onset Alzheimer’s disease (LOAD) beyond apolipoprotein E (APOE) but have not been leveraged to identify genetic resilience factors. Here, we sought to identify resilience-conferring common genetic variants in (1) unaffected individuals having high PRSs for LOAD, and (2) unaffected APOE-...
Article
Full-text available
Cerebellar volume is highly heritable and associated with neurodevelopmental and neurodegenerative disorders. Understanding the genetic architecture of cerebellar volume may improve our insight into these disorders. This study aims to investigate the convergence of cerebellar volume genetic associations in close detail. A genome-wide associations s...
Preprint
Schizophrenia (SCZ) and bipolar disorder (BD) are severe psychiatric conditions that can involve symptoms of psychosis and cognitive dysfunction. The two conditions share symptomatology, neuropathology, and genetic etiology and are thus regularly hypothesized to share underlying biology. Here we examined the effect of their combined genetic liabili...
Article
Insomnia is a heritable, highly prevalent sleep disorder for which no sufficient treatment currently exists. Previous genome-wide association studies with up to 1.3 million subjects identified over 200 associated loci. This extreme polygenicity suggested that many more loci remain to be discovered. The current study almost doubled the sample size t...
Preprint
Schizophrenia is a highly heritable developmental disorder with often devastating effects on patients and their families. The causal mechanisms behind SCZ remain largely unknown, even after more than a century of research. Astrocytes are increasingly being associated with neuropsychiatric disorders including schizophrenia, yet have gained little at...
Preprint
The functional connectivity and dynamics of resting-state networks (RSN-FC) are vital for cognitive functioning. RSN-FC is heritable and partially translates to the anatomical architecture of white matter, but the genetic component of structural connections of RSNs (RSN-SC) and their potential genetic overlap with RSN-FC remains unknown. Here we pe...
Preprint
Polygenic risk scores (PRSs) can boost risk-prediction in late-onset Alzheimer’s disease (LOAD) beyond apolipoprotein E ( APOE) but have not been leveraged to identify genetic resilience factors. Here, we sought to identify resilience-conferring common genetic variants in 1) unaffected individuals having high PRSs for LOAD, and 2) unaffected APOE -...
Article
Full-text available
We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enric...
Preprint
Full-text available
The widespread comorbidity among psychiatric disorders (PDs) demonstrated in epidemiological studies is mirrored by non-zero, positive genetic correlations from large scale genetic studies. We employed several strategies to uncover pleiotropic SNPs, genes and biological pathways underlying this genetic covariance. First, we conducted cross-trait me...
Preprint
Full-text available
Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, i...
Article
Genetic correlation (rg) analysis is used to identify phenotypes that may have a shared genetic basis. Traditionally, rg is studied globally, considering only the average of the shared signal across the genome, although this approach may fail when the rg is confined to particular genomic regions or in opposing directions at different loci. Current...
Article
With the rapidly increasing availability of large genetic data sets in recent years, Mendelian Randomization (MR) has quickly gained popularity as a novel secondary analysis method. Leveraging genetic variants as instrumental variables, MR can be used to estimate the causal effects of one phenotype on another even when experimental research is not...
Article
Genome-wide association studies (GWAS) test hundreds of thousands of genetic variants across many genomes to find those statistically associated with a specific trait or disease. This methodology has generated a myriad of robust associations for a range of traits and diseases, and the number of associated variants is expected to grow steadily as GW...
Article
Full-text available
Tourette syndrome (TS) is a highly heritable neuropsychiatric disorder with complex patterns of genetic inheritance. Recent genetic findings in TS have highlighted both numerous common variants with small effects and a few rare variants with moderate or large effects. Here we searched for genetic causes of TS in a large, densely-affected British pe...
Preprint
Full-text available
Despite the substantial heritability of antisocial behavior (ASB), specific genetic variants robustly associated with the trait have not been identified. The present study by the Broad Antisocial Behavior Consortium (BroadABC) meta-analyzed data from 25 discovery samples (N=85,359) and five independent replication samples (N = 8,058) with genotypic...
Preprint
We generated a proxy Alzheimer's disease phenotype for 148,508 individuals in the UK biobank in order to perform exome-wide rare variant aggregation analyses to identify genes associated with proxy Alzheimer's disease. We identified four genes significantly associated with the proxy phenotype, three of which have been previously associated with cli...
Article
Full-text available
Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar...
Article
Full-text available
A Correction to this paper has been published: https://doi.org/10.1038/s41380-021-01063-8
Preprint
Full-text available
Transcriptome-wide association studies (TWAS), which aim to detect relationships between gene expression and a phenotype, are commonly used for secondary analysis of genome-wide association study (GWAS) results. Results of TWAS analyses are often interpreted as indicating a genetically mediated relationship between gene expression and the phenotype...
Article
The use of induced pluripotent stem cells (iPSC) to model human complex diseases is gaining popularity as it allows investigation of human cells that are otherwise sparsely available. However, due to its laborious and cost intensive nature, iPSC research is often plagued by limited sample size and putative large variability between clones, decreasi...
Article
Neurological, cognitive and genetic sciences share a longstanding interest in studying the relationship between the shape of the human skull and of the brain. However, the downstream biological genetic underpinnings of such interactions, if they exist, remain largely unknown. A new genetic study now reports on a set of genes that may be involved in...
Article
Full-text available
Gene-environment interactions (GxE) are often suggested to play an important role in the aetiology of psychiatric phenotypes, yet so far, only a handful of genome-wide environment interaction studies (GWEIS) of psychiatric phenotypes have been conducted. Representing the most comprehensive effort of its kind to date, we used data from the UK Bioban...
Preprint
Full-text available
Here we report results from the Bipolar Exome (BipEx) collaboration analysis of whole exome sequencing of 13,933 individuals diagnosed with bipolar disorder (BD), matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in BD patients among genes under strong evolutionary constraint, a signal evident in both...
Article
Full-text available
An enigma in studies of neuropsychiatric disorders is how to translate polygenic risk into disease biology. For schizophrenia, where > 145 significant GWAS loci have been identified and only a few genes directly implicated, addressing this issue is a particular challenge. We used a combined cellomics and proteomics approach to show that polygenic r...
Preprint
Full-text available
Multiscale integration of neuroimaging and gene transcriptome is becoming a widely used approach for exploring the molecular pathways of brain structure and function, in health and disease. Statistical testing of associations between spatial patterns of imaging-based phenotypic and transcriptomic data is key in these explorations, in particular est...
Article
Full-text available
Background The etiology of frontotemporal dementia (FTD) is poorly understood. To identify genes with predicted expression levels associated with FTD, we integrated summary statistics with external reference gene expression data, using a transcriptome-wide association studies (TWAS) approach. Methods FUSION software was used to leverage FTD summar...
Preprint
Full-text available
Genetic correlation (rg) analysis is commonly used to identify traits that may have a shared genetic basis. Traditionally, rg is studied on a global scale, considering only the average of the shared signal across the genome; though this approach may fail to detect scenarios where the rg is confined to particular genomic regions, or show opposing di...
Preprint
With the rapidly increasing availability of large genetic data sets in recent years, Mendelian Randomization (MR) has quickly gained popularity as a novel secondary analysis method. Leveraging genetic variants as instrumental variables, MR can be used to estimate the causal effects of one phenotype on another even when experimental research is not...
Preprint
Full-text available
Insomnia is a heritable, highly prevalent sleep disorder, for which no sufficient treatment currently exists. Previous genome-wide association studies (GWASs) with up to 1.3 million subjects identified over 200 associated loci. This extreme polygenicity suggested many more loci to be discovered. The current study almost doubled the sample size to o...
Preprint
Full-text available
Late-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50-70% of dementia cases ¹ . Late-onset Alzheimer’s disease is caused by a combination of many genetic variants with small effect sizes and environmental influences. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have bee...
Article
Full-text available
The phenotypic correlation between human intelligence and brain volume (BV) is considerable (r ≈ 0.40), and has been shown to be due to shared genetic factors. To further examine specific genetic factors driving this correlation, we present genomic analyses of the genetic overlap between intelligence and BV using genome-wide association study (GWAS...
Preprint
Full-text available
Hi-C coupled multimarker analysis of genomic annotation (H-MAGMA) was initially developed to advance MAGMA by assigning non-coding SNPs to their cognate genes based on threedimensional chromatin architecture. Yurko and colleagues raised concerns that the SNP-wise mean gene-analysis model of MAGMA may allow inflation in type I errors. Accordingly, w...
Article
Full-text available
In this study we aimed to establish the genetic cause of a myriad of cardiovascular defects prevalent in individuals from a genetically isolated population, who were found to share a common ancestor in 1728. Trio genome sequencing was carried out in an index patient with critical congenital heart disease (CHD); family members had either exome or Sa...
Article
Full-text available
Neurodevelopmental disorders such as attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are highly heritable and influenced by many single nucleotide polymorphisms (SNPs). SNPs can be used to calculate individual polygenic risk scores (PRS) for a disorder. We aim to explore the association between the PRS for ADHD, A...
Preprint
Full-text available
The etiology of genetically sporadic frontotemporal dementia is poorly understood. Although genome-wide association studies for frontotemporal dementia have identified a small number of candidate risk regions, most of the risk genes remain largely unknown. To identify candidate genes with predicted expression levels associated with frontotemporal d...
Article
Full-text available
Background: Rett syndrome (RTT) is a progressive neurodevelopmental disease that is characterized by abnormalities in cognitive, social, and motor skills. RTT is often caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). The mechanism by which impaired MeCP2 induces the pathological abnormalities in the brain is...
Article
Full-text available
The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.
Article
Full-text available
Most neuropsychiatric disorders are highly polygenic, implicating hundreds to thousands of causal genetic variants that span across much of the genome. This widespread polygenicity complicates biological understanding because no single variant can explain disease etiology. A strategy to advance biological insight is to seek convergent functions amo...
Article
Full-text available
Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental disorders associated with cognitive impairment, which is considered a major determinant of functional outcome. Despite this, the etiology of the cognitive impairment is poorly understood, and no satisfactory cognitive treatments exist. Increasing evidence indicates that genetic risk fo...
Article
Full-text available
A correction to this paper has been published and can be accessed via a link at the top of the paper.
Article
Full-text available
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Preprint
Full-text available
Background Rett syndrome (RTT) is a progressive neurodevelopmental disease that is characterized by abnormalities in cognitive, social and motor skills. RTT is often caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). The mechanism by which impaired MeCP2 induces the pathological abnormalities in the brain is not...
Article
Full-text available
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Article
Full-text available
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Article
Genetic factors play a major role in Alzheimer’s disease (AD) pathology, but biological mechanisms through which these factors contribute to AD remain elusive. Using a cerebrospinal fluid (CSF) proteomic approach, we examined associations between polygenic risk scores for AD (PGRS) and CSF proteomic profiles in 250 individuals with normal cognition...
Preprint
Full-text available
Background Rett syndrome (RTT) is a progressive neurodevelopmental disease that is characterized by abnormalities in cognitive, social and motor skills. RTT is often caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). The mechanism by which impaired MeCP2 induces the pathological abnormalities in the brain is not...
Article
Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity...
Preprint
Full-text available
BACKGROUND: Disentangling the genetic constellation underlying Alzheimer's disease (AD) is important. Doing so allows us to identify biological pathways underlying AD, point towards novel drug targets and use the variants for individualised risk predictions in disease modifying or prevention trials. In the present work we report on the largest geno...
Article
Full-text available
Cognitive brain networks such as the default-mode network (DMN), frontoparietal network, and salience network, are key functional networks of the human brain. Here we show that the rapid evolutionary cortical expansion of cognitive networks in the human brain, and most pronounced the DMN, runs parallel with high expression of human-accelerated gene...
Article
Full-text available
Importance Psychotic experiences, such as hallucinations and delusions, are reported by approximately 5% to 10% of the general population, although only a small proportion develop psychotic disorders such as schizophrenia. Studying the genetic causes of psychotic experiences in the general population, and its association with the genetic causes of...
Article
Full-text available
After a decade of genome-wide association studies (GWASs), fundamental questions in human genetics, such as the extent of pleiotropy across the genome and variation in genetic architecture across traits, are still unanswered. The current availability of hundreds of GWASs provides a unique opportunity to address these questions. We systematically an...
Article
Full-text available
The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer’s disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurod...
Article
Full-text available
Single-cell RNA sequencing (scRNA-seq) data allows to create cell type specific transcriptome profiles. Such profiles can be aligned with genome-wide association studies (GWASs) to implicate cell type specificity of the traits. Current methods typically rely only on a small subset of available scRNA-seq datasets, and integrating multiple datasets i...