ABSTRACT
Mendelian disorders, arising from pathogenic variations within single genetic loci, often manifest as neurodevelopmental disorders (NDDs), affecting a significant portion of the pediatric population worldwide. These disorders are marked by atypical brain development, intellectual disabilities, and various associated phenotypic traits. Genetic testing aids in clinical diagnoses, but inconclusive results can prolong confirmation processes. Recent focus on epigenetic dysregulation has led to the discovery of DNA methylation signatures, or episignatures, associated with NDDs, accelerating diagnostic precision. Notably, TRIP12 and USP7, genes involved in the ubiquitination pathway, exhibit specific episignatures. Understanding the roles of these genes within the ubiquitination pathway sheds light on their potential influence on episignature formation. While TRIP12 acts as an E3 ligase, USP7 functions as a deubiquitinase, presenting contrasting roles within ubiquitination. Comparison of phenotypic traits in patients with pathogenic variations in these genes reveals both distinctions and commonalities, offering insights into underlying pathophysiological mechanisms. This review contextualizes the roles of TRIP12 and USP7 within the ubiquitination pathway, their influence on episignature formation, and the potential implications for NDD pathogenesis. Understanding these intricate relationships may unveil novel therapeutic targets and diagnostic strategies for NDDs.
ABSTRACT
Obesity represents a major public health emergency worldwide, and its etiology is shaped by a complex interplay of environmental and genetic factors. Over the last decade, polygenic risk scores (PRS) have emerged as a promising tool to quantify an individual's genetic risk of obesity. The field of PRS in obesity genetics is rapidly evolving, shedding new lights on obesity mechanisms and holding promise for contributing to personalized prevention and treatment. Challenges persist in terms of its clinical integration, including the need for further validation in large-scale prospective cohorts, ethical considerations, and implications for health disparities. In this review, we provide a comprehensive overview of PRS for studying the genetics of obesity, spanning from methodological nuances to clinical applications and challenges. We summarize the latest developments in the generation and refinement of PRS for obesity, including advances in methodologies for aggregating genome-wide association study data and improving PRS predictive accuracy, and discuss limitations that need to be overcome to fully realize its potential benefits of PRS in both medicine and public health.
ABSTRACT
In youth with posttraumatic stress disorder (PTSD) non-response rates after treatment are often high. Epigenetic mechanisms such as DNA methylation (DNAm) have previously been linked to PTSD pathogenesis, additionally DNAm may affect response to (psychological) therapies. Besides investigating the direct link between DNAm and treatment response, it might be helpful to investigate the link between DNAm and previously associated biological mechanisms with treatment outcome. Thereby gaining a deeper molecular understanding of how psychotherapy (reflecting a change in the environment) relates to epigenetic changes and the adaptability of individuals. To date, limited research is done in clinical samples and no studies have been conducted in youth. Therefore we conducted a study in a Dutch cohort of youth with and without PTSD (n = 87, age 8-18 years). We examined the cross-sectional and longitudinal changes of saliva-based genome-wide DNA methylation (DNAm) levels, and salivary cortisol secretion. The last might reflect possible abbreviations on the hypothalamic-pituitary- adrenal (HPA) axis. The HPA-axis is previously linked to DNAm and the development and recovery of PTSD. Youth were treated with 8 sessions of either Eye Movement Reprocessing Therapy (EMDR) or Trauma Focused Cognitive behavioral Therapy (TF-CBT). Our epigenome wide approach showed distinct methylation between treatment responders and non-responders on C18orf63 gene post-treatment. This genomic region is related to the PAX5 gene, involved in neurodevelopment and inflammation response. Additionally, our targeted approach indicated that there were longitudinal DNAm changes in successfully treated youth at the CRHR2 gene. Methylation at this gene was further correlated with cortisol secretion pre- and post-treatment. Awaiting replication, findings of this first study in youth point to molecular pathways involved in stress response and neuroplasticity to be associated with treatment response.
Subject(s)
DNA Methylation , Hydrocortisone , Saliva , Stress Disorders, Post-Traumatic , Humans , Stress Disorders, Post-Traumatic/therapy , Stress Disorders, Post-Traumatic/genetics , Stress Disorders, Post-Traumatic/metabolism , Saliva/metabolism , Saliva/chemistry , Male , Adolescent , Female , Child , Hydrocortisone/metabolism , Treatment Outcome , Cross-Sectional Studies , Eye Movement Desensitization Reprocessing , Epigenesis, Genetic , Hypothalamo-Hypophyseal System/metabolism , Netherlands , Pituitary-Adrenal System/metabolism , Longitudinal StudiesABSTRACT
The 16p11.2 deletion syndrome is a clinically heterogeneous disorder, characterized by developmental delay, intellectual disability, hyperphagia, obesity, macrocephaly and psychiatric problems. Cases with 16p11.2 duplication syndrome have similar neurodevelopmental problems, but typically show a partial 'mirror phenotype' with underweight and microcephaly. Various copy number variants (CNVs) of the chromosomal 16p11.2 region have been described. Most is known about the 'typical' 16p11.2 BP4-BP5 (29.6-30.2 Mb; ~600 kb) deletions and duplications, but there are also several published cohorts with more distal 16p11.2 BP2-BP3 CNVs (28.8-29.0 Mb; ~220 kb), who exhibit clinical overlap. We assessed 100 cases with various pathogenic 16p11.2 CNVs and compared their clinical characteristics to provide more clear genotype-phenotype correlations and raise awareness of the different 16p11.2 CNVs. Neurodevelopmental and weight issues were reported in the majority of cases. Cases with distal 16p11.2 BP2-BP3 deletion showed the most severe obesity phenotype (73.7% obesity, mean BMI SDS 3.2). In addition to the more well defined typical 16p11.2 BP4-BP5 and distal 16p11.2 BP2-BP3 CNVs, we describe the clinical features of five cases with other, overlapping, 16p11.2 CNVs in more detail. Interestingly, four cases had a second genetic diagnosis and 18 cases an additional gene variant of uncertain significance, that could potentially help explain the cases' phenotypes. In conclusion, we provide an overview of our Dutch cohort of cases with various pathogenic 16p11.2 CNVs and relevant second genetic findings, that can aid in adequately recognizing, diagnosing and counseling of individuals with 16p11.2 CNVs, and describe the personalized medicine for cases with these conditions.
ABSTRACT
Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by pathogenic variants in TCF4, leading to intellectual disability, specific morphological features, and autonomic nervous system dysfunction. Epigenetic dysregulation has been implicated in PTHS, prompting the investigation of a DNA methylation (DNAm) "episignature" specific to PTHS for diagnostic purposes and variant reclassification and functional insights into the molecular pathophysiology of this disorder. A cohort of 67 individuals with genetically confirmed PTHS and three individuals with intellectual disability and a variant of uncertain significance (VUS) in TCF4 were studied. The DNAm episignature was developed with an Infinium Methylation EPIC BeadChip array analysis using peripheral blood cells. Support vector machine (SVM) modeling and clustering methods were employed to generate a DNAm classifier for PTHS. Validation was extended to an additional cohort of 11 individuals with PTHS. The episignature was assessed in relation to other neurodevelopmental disorders and its specificity was examined. A specific DNAm episignature for PTHS was established. The classifier exhibited high sensitivity for TCF4 haploinsufficiency and missense variants in the basic-helix-loop-helix domain. Notably, seven individuals with TCF4 variants exhibited negative episignatures, suggesting complexities related to mosaicism, genetic factors, and environmental influences. The episignature displayed degrees of overlap with other related disorders and biological pathways. This study defines a DNAm episignature for TCF4-related PTHS, enabling improved diagnostic accuracy and VUS reclassification. The finding that some cases scored negatively underscores the potential for multiple or nested episignatures and emphasizes the need for continued investigation to enhance specificity and coverage across PTHS-related variants.
Subject(s)
DNA Methylation , Hyperventilation , Intellectual Disability , Transcription Factor 4 , Humans , Transcription Factor 4/genetics , Hyperventilation/genetics , Hyperventilation/diagnosis , Intellectual Disability/genetics , Intellectual Disability/diagnosis , Female , Male , Child , Facies , Adolescent , Epigenomics/methods , Epigenesis, Genetic , Hyperkinesis/genetics , Child, Preschool , Adult , Young AdultABSTRACT
PURPOSE: Hao-Fountain syndrome (HAFOUS) is a neurodevelopmental disorder caused by pathogenic variants in USP7. HAFOUS is characterized by developmental delay, intellectual disability, speech delay, behavioral abnormalities, autism spectrum disorder, seizures, hypogonadism, and mild dysmorphic features. We investigated the phenotype of 18 participants with HAFOUS and performed DNA methylation (DNAm) analysis, aiming to generate a diagnostic biomarker. Furthermore, we performed comparative analysis with known episignatures to gain more insight into the molecular pathophysiology of HAFOUS. METHODS: We assessed genomic DNAm profiles of 18 individuals with pathogenic variants and variants of uncertain significance (VUS) in USP7 to map and validate a specific episignature. The comparison between the USP7 cohort and 56 rare genetic disorders with earlier reported DNAm episignatures was performed with statistical and functional correlation. RESULTS: We mapped a sensitive and specific DNAm episignature for pathogenic variants in USP7 and utilized this to reclassify the VUS. Comparative epigenomic analysis showed evidence of HAFOUS similarity to a number of other rare genetic episignature disorders. CONCLUSION: We discovered a sensitive and specific DNAm episignature as a robust diagnostic biomarker for HAFOUS that enables VUS reclassification in USP7. We also expand the phenotypic spectrum of 9 new and 5 previously reported individuals with HAFOUS.
Subject(s)
Abnormalities, Multiple , Autism Spectrum Disorder , Bone Diseases, Developmental , Craniofacial Abnormalities , Deafness , Intellectual Disability , Neurodevelopmental Disorders , Humans , DNA Methylation/genetics , Autism Spectrum Disorder/genetics , Ubiquitin-Specific Peptidase 7/genetics , Epigenomics , Intellectual Disability/genetics , Intellectual Disability/diagnosis , Neurodevelopmental Disorders/genetics , Phenotype , BiomarkersABSTRACT
In this case report, we describe a rare prenatal finding of a small marker chromosome. This marker chromosome corresponds to an inverted duplication of the 13q region 13q31.1q34 (or 13q31.1 â qter) with a neocentromere, detected during genetic analysis of a chorionic villus sample in a fetus with multiple congenital anomalies after a normal prenatal screening result by noninvasive prenatal testing.
ABSTRACT
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 protein that is involved in the regulation of histone methyltransferase complexes. JARID2 plays a role in the epigenetic machinery, and the associated syndrome has an identified DNA methylation episignature derived from sequence variants and intragenic deletions involving JARID2. For this study, our aim was to determine whether patients with larger deletions spanning beyond JARID2 present a similar DNA methylation episignature and to define the critical region involved in aberrant DNA methylation in 6p22-p24 microdeletions. We examined the DNA methylation profiles of peripheral blood from 56 control subjects, 13 patients with (likely) pathogenic JARID2 variants or patients carrying copy number variants, and three patients with JARID2 VUS variants. The analysis showed a distinct and strong differentiation between patients with (likely) pathogenic variants, both sequence and copy number, and controls. Using the identified episignature, we developed a binary model to classify patients with the JARID2-neurodevelopmental syndrome. DNA methylation analysis indicated that JARID2 is the driver gene for aberrant DNA methylation observed in 6p22-p24 microdeletions. In addition, we performed analysis of functional correlation of the JARID2 genome-wide methylation profile with the DNA methylation profiles of 56 additional neurodevelopmental disorders. To conclude, we refined the critical region for the presence of the JARID2 episignature in 6p22-p24 microdeletions and provide insight into the functional changes in the epigenome observed when regulation by JARID2 is lost.
Subject(s)
Intellectual Disability , Neurodevelopmental Disorders , Humans , Genomics , Neurodevelopmental Disorders/genetics , Epigenome , Intellectual Disability/genetics , Epigenomics , Polycomb Repressive Complex 2/geneticsABSTRACT
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 study, we generated additional gene expression profiles in a subset of our previous FASD cohort, encompassing the most severely affected individuals, to examine the functional integrative effects of altered DNAm status on gene expression. We identified six differentially methylated regions (annotated to the SEC61G, REEP3, ZNF577, HNRNPF, MSC, and SDHAF1 genes) associated with changes in gene expression (p-value < 0.05). To the best of our knowledge, this study is the first to assess whole blood gene expression and DNAm-gene expression associations in FASD. Our results present novel insights into the molecular footprint of FASD in whole blood and opens opportunities for future research into multi-omics biomarkers for the diagnosis of FASD.
Subject(s)
Fetal Alcohol Spectrum Disorders , Prenatal Exposure Delayed Effects , Humans , Female , Pregnancy , Fetal Alcohol Spectrum Disorders/diagnosis , Fetal Alcohol Spectrum Disorders/genetics , Prenatal Exposure Delayed Effects/genetics , Phenotype , DNA Methylation , Biomarkers , SEC Translocation Channels/geneticsABSTRACT
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 diagnostic biomarker and gain functional insights into the molecular pathophysiology of HNRNPU-related disorder. METHODS: DNAm profiles of individuals carrying pathogenic HNRNPU variants, identified through an international multicenter collaboration, were assessed using Infinium Methylation EPIC arrays. Statistical and functional correlation analyses were performed comparing the HNRNPU cohort with 56 previously reported DNAm episignatures. RESULTS: A robust and reproducible DNAm episignature and global DNAm profile were identified. Correlation analysis identified partial overlap and similarity of the global HNRNPU DNAm profile to several other rare disorders. CONCLUSION: This study demonstrates new evidence of a specific and sensitive DNAm episignature associated with pathogenic heterozygous HNRNPU variants, establishing its utility as a clinical biomarker for the expansion of the EpiSign diagnostic test.
Subject(s)
DNA Methylation , Neurodevelopmental Disorders , Humans , DNA Methylation/genetics , Epigenomics , Phenotype , Neurodevelopmental Disorders/genetics , Neurodevelopmental Disorders/pathology , BiomarkersABSTRACT
BACKGROUND: Congenital anomalies represent an important global health issue. Data on the prevalence and pattern of congenital anomalies in the Caribbean region are scarce and lacking altogether in Aruba, Bonaire and Curaçao (ABC islands). METHODS: We performed a population-based surveillance study to determine the prevalence of structural congenital anomalies in the ABC islands, including all live births and stillbirths between January 1, 2008 and December 31, 2017 with major congenital anomalies according to EUROCAT guide 1.5. Terminations of pregnancy for fetal anomaly were included as well. Cases were identified by active case ascertainment, using multiple sources including pediatric patient files and discharge letters, delivery records, and clinical genetic patient files. Total and subgroup prevalence rates were compared between the three islands and to the French West Indies and Northern Netherlands. RESULTS: Total prevalence of congenital anomalies on the ABC islands was 242.97 per 10,000 births. Total prevalence of congenital anomalies in Bonaire (325.15 per 10,000 births) was higher compared to Aruba (233.29 per 10,000 births) and Curaçao (238.58 per 10,000 births), which was mainly attributable to a higher prevalence of limb anomalies, in particular polydactyly, in Bonaire. Total prevalence of congenital anomalies on the ABC islands was comparable to the French West Indies (248.69 per 10,000 births) but significantly lower compared to the Northern Netherlands (298.98 per 10,000 births). In the subgroup prevalence analysis, the prevalence of polydactyly and atrial septal defect on the ABC islands was significantly higher compared with the French West Indies and the Northern Netherlands, while the prevalence of congenital anomalies of the kidney and urinary tract and genetic disorders was significantly lower. CONCLUSIONS: This is the first study to establish the prevalence and pattern of congenital anomalies on the ABC islands, which is important to inform healthcare managers and policymakers and to provide a basis for continuous surveillance of congenital anomalies.
Subject(s)
Polydactyly , Pregnancy , Female , Humans , Child , Aruba , Curacao , Prevalence , Caribbean Netherlands , West Indies/epidemiologyABSTRACT
PURPOSE: Pathogenic variants in genes involved in the epigenetic machinery are an emerging cause of neurodevelopment disorders (NDDs). Lysine-demethylase 2B (KDM2B) encodes an epigenetic regulator and mouse models suggest an important role during development. We set out to determine whether KDM2B variants are associated with NDD. METHODS: Through international collaborations, we collected data on individuals with heterozygous KDM2B variants. We applied methylation arrays on peripheral blood DNA samples to determine a KDM2B associated epigenetic signature. RESULTS: We recruited a total of 27 individuals with heterozygous variants in KDM2B. We present evidence, including a shared epigenetic signature, to support a pathogenic classification of 15 KDM2B variants and identify the CxxC domain as a mutational hotspot. Both loss-of-function and CxxC-domain missense variants present with a specific subepisignature. Moreover, the KDM2B episignature was identified in the context of a dual molecular diagnosis in multiple individuals. Our efforts resulted in a cohort of 21 individuals with heterozygous (likely) pathogenic variants. Individuals in this cohort present with developmental delay and/or intellectual disability; autism; attention deficit disorder/attention deficit hyperactivity disorder; congenital organ anomalies mainly of the heart, eyes, and urogenital system; and subtle facial dysmorphism. CONCLUSION: Pathogenic heterozygous variants in KDM2B are associated with NDD and a specific epigenetic signature detectable in peripheral blood.
Subject(s)
Intellectual Disability , Neurodevelopmental Disorders , Mice , Animals , Humans , DNA Methylation/genetics , Neurodevelopmental Disorders/genetics , Intellectual Disability/genetics , DNA , MutationABSTRACT
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 sorting of proteins. This enzymatic pathway is crucial for physiological processes. A significant proportion of TRIP12 variants are currently classified as variants of unknown significance (VUS). Episignatures have been shown to represent a powerful diagnostic tool to resolve inconclusive genetic findings for Mendelian disorders and to re-classify VUSs. Here, we show the results of DNA methylation episignature analysis in 32 individuals with pathogenic, likely pathogenic and VUS variants in TRIP12. We identified a specific and sensitive DNA methylation (DNAm) episignature associated with pathogenic TRIP12 variants, establishing its utility as a clinical biomarker for Clark-Baraitser syndrome. In addition, we performed analysis of differentially methylated regions as well as functional correlation of the TRIP12 genome-wide methylation profile with the profiles of 56 additional neurodevelopmental disorders.
Subject(s)
Mental Retardation, X-Linked , Humans , Facies , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism , Ubiquitin/metabolism , Carrier Proteins/metabolismABSTRACT
Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals-16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-ß precursor protein processing, amyloid-ß aggregation, lipid metabolism and microglial function in AD.
Subject(s)
ATP Binding Cassette Transporter 1 , Adenosine Triphosphatases , Alzheimer Disease , Exosomes , Humans , Adenosine Triphosphatases/genetics , Alzheimer Disease/genetics , ATP Binding Cassette Transporter 1/genetics , Genome-Wide Association Study , Risk Factors , Exosomes/geneticsABSTRACT
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 histone methyltransferase complexes. However, the molecular etiology is not fully understood, and JARID2-neurodevelopmental syndrome may vary in its typical clinical phenotype. In addition, the detection of variants of uncertain significance (VUSs) often results in a delay of final diagnosis which could hamper the appropriate care. In this study we aim to detect a specific and sensitive DNA methylation signature for JARID2-neurodevelopmental syndrome. Peripheral blood DNA methylation profiles from 56 control subjects, 8 patients with (likely) pathogenic JARID2 variants and 3 patients with JARID2 VUSs were analyzed. DNA methylation analysis indicated a clear and robust separation between patients with (likely) pathogenic variants and controls. A binary model capable of classifying patients with the JARID2-neurodevelopmental syndrome was constructed on the basis of the identified episignature. Patients carrying VUSs clustered with the control group. We identified a distinct DNA methylation signature associated with JARID2-neurodevelopmental syndrome, establishing its utility as a biomarker for this syndrome and expanding the EpiSign diagnostic test.
Subject(s)
DNA Methylation , Polycomb Repressive Complex 2 , Humans , Nucleotide Motifs , Phenotype , Polycomb Repressive Complex 2/genetics , Protein Processing, Post-Translational , SyndromeABSTRACT
Worldwide, there are large inequalities in genetic service delivery. In 2011, we established a bi-annual joint pediatric-genetics clinic with a visiting clinical geneticist in the Dutch Caribbean. This retrospective study evaluates the yield of diagnostic testing and the clinical utility of a diagnosis for patients with rare diseases on these relatively isolated, resource-limited islands. A total of 331 patients that were referred to the clinical geneticist between November 2011 and November 2019 and had genetic testing were included in this study. A total of 508 genetic tests were performed on these patients. Microarray, next-generation sequencing gene panels, and single-gene analyses were the most frequently performed genetic tests. A molecularly confirmed diagnosis was established in 33% of patients (n = 108). Most diagnosed patients had single nucleotide variants or small insertions and/or deletions (48%) or copy number variants (34%). Molecular diagnostic yield was highest in patients referred for seizures and developmental delay/intellectual disability. The genetic diagnosis had an impact on clinical management in 52% of patients. Referrals to other health professionals and changes in therapy were the most frequently reported clinical consequences. In conclusion, despite limited financial resources, our genetics service resulted in a reasonably high molecular diagnostic yield. Even in this resource-limited setting, a genetic diagnosis had an impact on clinical management for the majority of patients. Our approach with a visiting clinical geneticist may be an example for others who are developing genetic services in similar settings.
Subject(s)
DNA Copy Number Variations , Intellectual Disability , Caribbean Region/epidemiology , Child , Genetic Testing/methods , Humans , Intellectual Disability/genetics , Retrospective StudiesABSTRACT
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 linked to CVD in previous reports, or to estimated CVD risk in the same population. We used the Illumina Infinium® HumanMethylation450 BeadChip to obtain DNAm profiles of blood samples in 589 Ghanaians from the RODAM study (without acute infections, not taking anti-inflammatory medications, CRP levels < 40 mg/L). We then used linear models to identify DMPs associated with CRP concentrations. Post-hoc, we evaluated associations of identified DMPs with elevated CVD risk estimated via ASCVD risk score. We also performed subset analyses at CRP levels ≤10 mg/L and replication analyses on candidate probes. Finally, we assessed for biological relevance of our findings in public databases. We subsequently identified 14 novel DMPs associated with CRP. In post-hoc evaluations, we found that DMPs in PC, BTG4 and PADI1 showed trends of associations with estimated CVD risk, we identified a separate DMP in MORC2 that was associated with CRP levels ≤10 mg/L, and we successfully replicated 65 (24%) of previously reported DMPs. All DMPs with gene annotations (13) were biologically linked to inflammation or CVD traits. We have identified epigenetic loci that may play a role in the intersection between inflammation and CVD among Ghanaians. Further studies among other Africans are needed to confirm our findings.
ABSTRACT
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 pathogenesis. We performed concurrent whole-genome bisulphite sequencing and RNA-Sequencing on synovial tissue obtained from the knee and ankle from 4 auto-antibody positive arthralgia patients and thirteen RA patients. Through multi-omics factor analysis we observed that the latent factor explaining the variance in gene expression and DNA methylation was associated with Swollen Joint Count 66 (SJC66), with patients with SJC66 of 9 or more displaying separation from the rest. Interrogating these observed differences revealed activation of the immune response as well as dysregulation of cell adhesion pathways at the level of both DNA methylation and gene expression. We observed differences for 59 genes in particular at the level of both transcript expression and DNA methylation. Our results highlight the utility of genome-wide multi-omics profiling of synovial samples for improved understanding of changes associated with disease spread in arthralgia and RA patients, and point to novel candidate targets for the treatment of the disease.
Subject(s)
Arthralgia/immunology , Arthritis, Rheumatoid/complications , DNA Methylation/immunology , Epigenesis, Genetic/immunology , Synovial Membrane/pathology , Adult , Aged , Aged, 80 and over , Arthralgia/genetics , Arthralgia/pathology , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/pathology , Arthroscopy , Biopsy/methods , Female , Humans , Male , Middle Aged , RNA-Seq , Severity of Illness Index , Synovial Membrane/immunology , Whole Genome Sequencing , Young AdultABSTRACT
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 study, we combined a methylome-wide association study and structural neuroimaging measures in a Dutch cohort of youths with PTSD (8-18 years of age). We aimed to replicate findings in a similar independent U.S. cohort. RESULTS: We found significant methylome-wide associations for pediatric PTSD (false discovery rate p < .05) compared with non-PTSD control groups (traumatized and nontraumatized youths). Methylation differences on nine genes were replicated, including genes related to glucocorticoid functioning. In both cohorts, methylation on OLFM3 gene was further associated with anterior hippocampal volume. CONCLUSIONS: These findings point to molecular pathways involved in inflammation, stress response, and neuroplasticity as potential contributors to neural abnormalities and provide potentially unique biomarkers and treatment targets for pediatric PTSD.
Subject(s)
Stress Disorders, Post-Traumatic , Adolescent , Brain , Child , DNA Methylation , Epigenesis, Genetic , Hippocampus , Humans , Stress Disorders, Post-Traumatic/geneticsABSTRACT
The Caribbean part of the Kingdom of the Netherlands consists of six islands: Aruba, Bonaire, Curaçao, St. Maarten, St. Eustatius, and Saba. Because of their small size and relative remoteness, they face several economic and healthcare challenges, including limited access to genetics services. In this article, we provide an overview of the clinical and community genetics services that are available in the Dutch Caribbean. In particular, we describe our joint pediatric-genetics clinic with a visiting clinical geneticist that was established in 2011 to provide clinical genetics services for the pediatric population of the Dutch Caribbean.