Peter Henneman

Amsterdam University Medical Centers · Human Genetics

JARID2 (Jumonji, AT-rich interactive domain 2) haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome. It is characterized by intellectual disability, developmental delay, autistic features, behavior abnormalities, cognitive impairment, hypotonia, and dysmorphic features. JARID2 acts as a transcriptional repressor p...

Introduction: Predictive biomarkers for treatment efficacy of ulcerative colitis (UC) treatments are lacking. Here, we performed a longitudinal study investigating the association and potential predictive power of genome-wide peripheral blood (PB) DNA methylation signatures and response to tofacitinib treatment in UC. Methods: We recruited moder...

Background & Aims. Vedolizumab (VDZ) is a monoclonal antibody approved for the treatment of Crohn's disease (CD) by abrogating the gut-homing behavior of various leukocytes. Despite its efficacy, non-response to VDZ is common in clinical practice. Here, we performed an observational case-control study to interrogate the differences between responde...

Background Despite the proven efficacy of biological treatments in Crohn’s disease (CD), many patients fail to respond or lose response over time. Therefore, predictive biomarkers for treatment efficacy would be of extreme value. Previous epigenome-wide association studies associated differential DNA methylation with CD-specific phenotypes, suggest...

Objective The epigenetic regulation of the renin-angiotensin-aldosterone system (RAAS) potentially plays a role in the pathophysiology underlying the high burden of hypertension in sub-Saharan Africans (SSA). In this first epigenome-wide association study (EWAS) of plasma renin and aldosterone concentrations, we explored the association between DNA...

Objective Sub-Saharan African (SSA) migrants are disproportionately affected by hypertension, compared to the European-host population. Underlying reasons for the increased hypertension prevalence are still unclear, but suggest that rapid changes in lifestyle and environment after migration, in combination with genetic factors, might be responsible...

Purpose; HNRNPU haploinsufficiency is associated with Developmental and Epileptic Encephalopathy 54. This neurodevelopmental disorder is characterized by developmental delay, intellectual disability, speech impairment, and early onset epilepsy. We performed genome-wide DNA methylation (DNAm) analysis in a cohort of individuals to develop a diagnost...

Fetal alcohol spectrum disorder (FASD) encompasses neurodevelopmental disabilities and physical birth defects associated with prenatal alcohol exposure. Previously, we attempted to identify epigenetic biomarkers for FASD by investigating the genome-wide DNA methylation (DNAm) profiles of individuals with FASD compared to healthy controls. In this s...

Background: DNA-methylation has been associated with plasma lipid concentration in populations of diverse ethnic backgrounds, but epigenome-wide association studies (EWAS) in West-Africans are lacking. The aim of this study was to identify DNA-methylation loci associated with plasma lipids in Ghanaians. Methods: We conducted an EWAS using Illumina...

Background Despite the proven efficacy of biological treatments in Crohn’s disease (CD), many patients fail to respond or lose response over time. Therefore, predictive biomarkers for treatment efficacy would be of extreme value. Previous epigenome-wide association studies associated differential DNA methylation with CD-specific phenotypes, suggest...

In this review we discuss epigenetic disorders that result from aberrations in genes linked to epigenetic regulation. We describe current testing methods for the detection of copy number variants (CNVs) in Mendelian disorders, dosage sensitivity, reciprocal phenotypes and the challenges of test selection and overlapping clinical features in genetic...

Purpose The Research on Obesity and Diabetes among African Migrants (RODAM) prospective (RODAM-Pros) cohort study was established to identify key changes in environmental exposures and epigenetic modifications driving the high burden of cardiovascular disease (CVD) risk among sub-Saharan African migrants. Participants All the participants in the R...

Background African Americans have a high risk for type 2 diabetes (T2D) and insulin resistance. Studies among other population groups have identified DNA methylation loci associated with insulin resistance, but data in African Americans are lacking. Using DNA methylation profiles of blood samples obtained from the Illumina Infinium® HumanMethylatio...

Background The epigenetic regulation of the renin–angiotensin–aldosterone system (RAAS) potentially plays a role in the pathophysiology underlying the high burden of hypertension in sub-Saharan Africans (SSA). Here we report the first epigenome-wide association study (EWAS) of plasma renin and aldosterone concentrations and the aldosterone-to-renin...

Background & Aims There is great current interest in the potential application of DNA methylation alterations in peripheral blood leukocytes (PBL) as biomarkers of susceptibility, progression and treatment response in inflammatory bowel disease (IBD). However, the intra-individual stability of PBL methylation in IBD has not been characterised. Here...

Clark–Baraitser syndrome is a rare autosomal dominant intellectual disability syndrome caused by pathogenic variants in the TRIP12 (Thyroid Hormone Receptor Interactor 12) gene. TRIP12 encodes an E3 ligase in the ubiquitin pathway. The ubiquitin pathway includes activating E1, conjugating E2 and ligating E3 enzymes which regulate the breakdown and...

Background: In Down syndrome (DS) there is a high occurrence of congenital hypothyroidism (CH) and subclinical hypothyroidism (SH) early in life. The etiology of CH and early SH in DS remains unclear. Previous research has shown genome-wide transcriptional and epigenetic alterations in DS. Thus, we hypothesized that CH and early SH could be caused...

Background: In Down syndrome (DS) there is a high occurrence of congenital hypothyroidism (CH) and subclinical hypothyroidism (SH) early in life. The etiology of CH and early SH in DS remains unclear. Previous research has shown genome-wide transcriptional and epigenetic alterations in DS. Thus, we hypothesized that CH and early SH could be caused...

Prediction of endoscopic post-operative recurrence (POR) in Crohn’s disease (CD) patients following ileocolonic resection (ICR) using clinical risk factors alone has thus far been inadequate. While peripheral blood leukocyte (PBL) DNA methylation has shown promise as a tool for predicting recurrence in cancer, no data in CD patients exists. Therefo...

Background and Aims Over the past decade, the DNA methylome has been increasingly studied in peripheral blood of inflammatory bowel disease (IBD) patients. However, a comprehensive summary and meta-analysis of peripheral blood leukocyte (PBL) DNA methylation studies has thus far not been conducted. Here, we systematically reviewed all available lit...

Introduction There is great current interest in the potential application of DNA methylation alterations in peripheral blood leukocytes (PBL) as biomarkers of susceptibility, progression and treatment response in inflammatory bowel disease (IBD). However, the intra–individual stability of PBL methylation in IBD has not been characterised. Here, we...

Background SP140 is a bromodomain-containing protein expressed predominantly in immune cells. Genetic polymorphisms and epigenetic modifications in the SP140 locus have been linked to Crohn’s disease (CD), suggesting a role in inflammation. Results We report the development of the first small molecule SP140 inhibitor (GSK761) and utilize this to e...

JARID2 (Jumonji, AT Rich Interactive Domain 2) pathogenic variants cause a neurodevelopmental syndrome, that is characterized by developmental delay, cognitive impairment, hypotonia, autistic features, behavior abnormalities and dysmorphic facial features. JARID2 encodes a transcriptional repressor protein that regulates the activity of various his...

Methylation tests have been used for decades in regular DNA diagnostics focusing primarily on Imprinting disorders or specific loci annotated to specific disease associated gene promotors. With the introduction of DNA methylation (DNAm) arrays such as the Illumina Infinium HumanMethylation450 Beadchip array or the Illumina Infinium Methylation EPIC...

An expanding range of genetic syndromes are characterized by genome‐wide disruptions in DNA methylation profiles referred to as episignatures. Episignatures are distinct, highly sensitive and specific biomarkers that have recently been applied in clinical diagnosis of genetic syndromes. Episignatures are contained within the broader disorder‐specif...

References 1. Verberne EA, Goh S, England J, van Ginkel M, Rafael-Croes L, et al. JARID2 Haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome. Genet Med. 2021;23(2):374-83.

Aim: To detect expression quantitative trait methylation (eQTM) loci within the cerebrum of prenatal Down syndrome (DS) and controls. Material & methods: DNA methylation gene expression profiles were acquired from NeuN+ nuclei, obtained from cerebrum sections of DS and controls. Linear regression models were applied to both datasets and were subseq...

Background Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease affecting the intra- and extrahepatic bile ducts, and is strongly associated with ulcerative colitis (UC). In this study, we explored the peripheral blood DNA methylome and its immune cell composition in patients with PSC-UC, UC, and healthy controls (HC) with t...

Background While Vedolizumab (VDZ) is an established treatment for Crohn’s disease (CD), primary non-response is well-recognised – there is an urgent clinical need for biomarkers that predict response, before initiation of treatment. Metabolomic profiling is a rapidly growing field in biomarker discovery and can distinguish between active and quies...

Background Despite the proven efficacy of vedolizumab (VDZ), only 29% and 36% of the Crohn’s disease (CD) patients present corticosteroid-free clinical- and endoscopic remission, respectively. Therefore, predictive biomarkers for treatment success would be of extreme value. Previous studies have identified aberrant DNA methylation associated with C...

Background Crohn’s disease (CD) is a complex disease where the gut microbiome plays an important role. One of the established treatments in CD is Vedolizumab (VDZ), an alpha(4)beta(7) integrin antibody. Finding biomarkers to predict therapy response is still a clinical unmet need, since this treatment has shown endoscopic remission in only a third...

Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we...

Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated...

Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate...

Molecular mechanisms at the intersection of inflammation and cardiovascular diseases (CVD) among Africans are still unknown. We performed an epigenome-wide association study to identify loci associated with serum C-reactive protein (marker of inflammation) among Ghanaians and further assessed whether differentially methylated positions (DMPs) were...

Background Migraine is a common brain disorder but reliable diagnostic biomarkers in blood are still lacking. Our aim was to identify, using proton nuclear magnetic resonance (¹H-NMR) spectroscopy, metabolites in serum that are associated with lifetime and active migraine by comparing metabolic profiles of patients and controls. Methods Fasting se...

Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study we...

Accumulating evidence shows that microbes with their theater of activity residing within the human intestinal tract (i.e., the gut microbiome) influence host metabolism. Some of the strongest results come from recent fecal microbial transplant (FMT) studies that relate changes in intestinal microbiota to various markers of metabolism as well as the...

Background: Recent findings in neuroimaging and epigenetics offer important insights into brain structures and biological pathways of altered gene expression associated with posttraumatic stress disorder (PTSD). However, it is unknown to what extent epigenetic mechanisms are associated with PTSD and its neurobiology in youth. Methods: In this st...

Background: African populations are experiencing health transitions due to rapid urbanization and international migration. However, the role of biological aging in this emerging burden of cardiometabolic diseases (CMD) among migrant and non-migrant Africans is unknown. We aimed to examine differences in epigenetic age acceleration (EAA) as measure...

Aim: We assessed epigenome-wide DNA methylation (DNAm) differences between migrant and non-migrant Ghanaians. Materials & methods: We used the Illumina Infinium® HumanMethylation450 BeadChip to profile DNAm of 712 Ghanaians in whole blood. We used linear models to detect differentially methylated positions (DMPs) associated with migration. We perfo...

In this study, we sought to characterize synovial tissue obtained from individuals with arthralgia and disease-specific auto-antibodies and patients with established rheumatoid arthritis (RA), by applying an integrative multi-omics approach where we investigated differences at the level of DNA methylation and gene expression in relation to disease...

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disorder characterized by disabling fatigue. Several studies have sought to identify diagnostic biomarkers, with varying results. Here, we innovate this process by combining both mRNA expression and DNA methylation data. We performed recursive ensemble feature selection (REFS)...

Purpose We describe the clinical implementation of genome-wide DNA methylation analysis in rare disorders across the EpiSign diagnostic laboratory network and the assessment of results and clinical impact in the first subjects tested. Methods We outline the logistics and data flow between an integrated network of clinical diagnostics laboratories...

A Correction to this paper has been published: https://doi.org/10.1038/s41436-021-01130-z

Background Familial hypercholesterolemia (FH) is a monogenic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C). A FH causing genetic variant in LDLR, APOB, or PCSK9 is not identified in 12–60% of clinical FH patients (FH mutation-negative patients). We aimed to assess whether altered DNA methylation might be associated...

Histone deacetylases (HDACs) are a group of enzymes that control histone deacetylation and bear potential to direct expression of large gene sets. We determined the effect of HDAC inhibitors (HDACi) on human monocytes and macrophages, with respect to their polarization, activation, and their capabilities of inducing endotoxin tolerance. To address...

Recent findings in neuroimaging and epigenetics offer important insights into brain structures and biological pathways of altered gene expression associated with posttraumatic stress disorder (PTSD). However, it is unknown to what extent epigenetic mechanisms are associated with PTSD and its neurobiology in youth. Therefore, we combine genome-wide...

SP140 is a bromodomain-containing protein expressed predominantly in immune cells. Genetic polymorphisms and epigenetic modifications in the SP140 locus have been linked to Crohn's disease (CD), suggesting a role in inflammation. We report the development of the first small molecule SP140 inhibitor (GSK761) and utilize this to elucidate SP140 funct...

Crohn’s disease (CD) is a multifactorial incurable chronic disorder. Current medical treatment seeks to induce and maintain a state of remission. During episodes of inflammation, monocytes infiltrate the inflamed mucosa whereupon they differentiate into macrophages with a pro-inflammatory phenotype. Here, we sought to characterize the circulating m...

Sub-Saharan African (SSA) migrants in Europe experience psychosocial stressors, such as perceived discrimination (PD). The effect of such a stressor on health could potentially be mediated via epigenetics. In this study we performed an epigenome-wide association study (EWAS) to assess the association between levels of PD with genome-wide DNA methyl...

Autologous transplantation of spermatogonial stem cells is a promising new avenue to restore fertility in infertile recipients. Expansion of the initial spermatogonial stem cell pool through cell culturing is a necessary step to obtain enough cells for effective repopulation of the testis after transplantation. Since in vitro propagation can lead t...

Crohn's disease (CD) is a multifactorial incurable chronic disorder. Current medical treatment seeks to induce and maintain a state of remission. During episodes of inflammation, monocytes infiltrate inflamed mucosa whereupon they differentiate into macrophages with a pro-inflammatory phenotype. Here, we sought to characterize the circulating monoc...

Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called “episignatures”). Peripheral blood episignatures can be...

Background While the use of biologicals has revolutionised the treatment of Crohn’s disease (CD) in recent decades, many patients fail to respond or lose response over time. Predictors for treatment selection and/or success are lacking. Vedolizumab (VDZ) induces corticosteroid-free clinical remission in 29% and endoscopic remission in 36% of patien...

Background SP140 (Speckled 140 KDa) encodes an epigenetic reader protein with an immune restricted expression, that binds to epigenetically modified (acetylated and methylated) histones and thereby regulates expression of large gene sets, including pro-inflammatory cytokines, in innate immune cells. SP140 is implicated in CD because single nucleoti...

Macrophages are heterogeneous leukocytes regulated in a tissue- and disease-specific context. While in vitro macrophage models have been used to study diseases empirically, a systematic analysis of the transcriptome thereof is lacking. Here, we acquired gene expression data from eight commonly-used in vitro macrophage models to perform a meta-analy...

Objective: In the advent of rapid urbanization, migration and epidemiological transition, the extent to which serum uric acid (sUA) affects cardiovascular disease (CVD) risk among Africans is not well understood. We assessed differences in sUA levels and associations with CVD risk among migrant Ghanaians in Europe, and non-migrant Ghanaians in rur...

SETD1B is a component of a histone methyltransferase complex that specifically methylates Lys-4 of histone H3 (H3K4) and is responsible for the epigenetic control of chromatin structure and gene expression. De novo microdeletions encompassing this gene as well as de novo missense mutations were previously linked to syndromic intellectual disability...

Objective In the advent of rapid urbanization, migration and epidemiological transition, the extent to which serum uric acid (sUA) affects cardiovascular disease (CVD) risk among Africans is not well understood. We assessed differences in sUA levels and associations with estimated CVD risk among migrant Ghanaians in Europe, and non-migrant Ghanaian...

Background: Exposure to adverse conditions earlier in life-course can predispose to type 2 diabetes in adulthood, irrespective of body mass index (BMI). However, the burden of type 2 diabetes in lean Africans is not well understood despite higher exposure to adverse early life conditions. Mirroring ongoing epidemiological transition, we assessed t...

Purpose of Review The metabolic syndrome is a pathological state in which one of the key components is insulin resistance. A wide spectrum of body compartments is involved in its pathophysiology. Genetic and environmental factors such as diet and physical activity are both related to its etiology. Reversible modulation of gene expression without al...