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Could monitoring methylation markers aid the management of schizophrenia? “The unique properties of DNA methylation in combination with rapidly developing laboratory technologies position methylomics research as a particularly promising biomarker platform in the near future.” Keywords: biomarkers • DNA methylation • MBD-seq • methylome-wide association study • MWAS • schizophrenia
Schizophrenia Schizophrenia is a devastating psychiatric condition [1] . Its median lifetime prevalence is 0.7–0.8%. Patients experience hallucinations and delusion as well as impairment in both basic sensory processing and higher cognitive function such as reasoning and planning [2] . Onset is typically in adolescence/early adulthood and the course of illness is characterized by exacerbations, remissions and relapses. Schizophrenia is typically diagnosed using the Diagnostic and Statistical Manual of Mental Disorders (DSM) or the International Classification of Disease (ICD). However, rather than being a single disease entity, it may be a set of several disorders sharing clinical features but having (partly) different underlying causes [3] . These subtypes may be distinguishable from each other with respect to prognosis, course or treatment response. Although the available schizophrenia pharmacotherapies often lack efficacy and/or cause side effects in a substantial group of patients, few new drugs are under development [4] . Therefore, the ability to use biomarkers to better diagnose and optimize existing treatments would be of tremendous clinical value. DNA methylation Epigenetic modifications refer to changes in the DNA that do not involve the nucleotide sequence. One of the most intensively studied modifications is the methylation of DNA cytosine residues at the carbon 5 position. In human (non-stem cell) DNA, this epigenetic mark is mainly found in the sequence context
10.2217/BMM.14.44 © 2014 Future Medicine Ltd
of CpG. DNA methylation can directly affect gene regulation. It is essential for normal cell functioning, and is playing an important role in, for example, brain development [5] . Indeed, aberrant methylation has been associated with a variety of human diseases, including psychiatric conditions [6–8] . Methylation sites as biomarkers Methylation studies particularly offer promise to improve schizophrenia disease management. First, methylation markers may have better predictive power than genetic markers as methylation can directly affect gene regulation. Second, methylation studies may improve disease understanding as they can potentially account for a wide range of clinical features of schizophrenia such as individual differences in course and episodicity. Third, methylation marks are potential drug targets as they are modifiable by pharma ceutical interventions. Finally, as these marks are stable in collected biomaterial, and can be measured cost-effectively in biosamples that are easy to collect such as blood, they are well suited for eventual use in the clinical setting. Concrete examples of potential use include: • Diagnosis: different disease causes may leave different methylation signatures. Methylation marks could therefore potentially help to diagnose etiologically distinct subtypes; • Treatment: methylation as a (early) marker of treatment response can be used to personalize and optimize pharmacotherapy;
Biomarkers Med. (2014) 8(5), 607–611
Karolina A Aberg Author for correspondence: Center for Biomarker Research & Personalized Medicine, Virginia Commonwealth University, VA 23298, USA Tel.: +1 804 628 3023 Fax: +1 804 628 3991 kaaberg@ vcu.edu
Edwin JCG van den Oord Center for Biomarker Research & Personalized Medicine, Virginia Commonwealth University, VA 23298, USA
part of
ISSN 1752-0363
609
Editorial Aberg & van den Oord • Prognosis: an accumulation of evidence from animal and human research demonstrates that alterations in methylation can be persistent over time and have long-term phenotypic consequences [9] . Methylation could therefore predict risks of specific symptom developments and chronicity of the disease. Methylation biomarkers in blood The pathogenic processes for psychiatric disorders likely involve the brain. Although it is advantageous to investigate a methylation mark directly in the most relevant tissue, procurement of brain tissue is typically not possible. Given that blood is easy to collect, with very limited risk to the patient, it is an appealing alternative tissue. There are two models explaining how methylation marks in blood could yield useful biomarkers [10] . It should be noted that neither model assumes that methylation in blood directly affects disease susceptibility. In the ‘signature model’ associations between schizophrenia and methylation marks occur because factors that increase disease susceptibility leave a biomarker signature in blood. Thus, the methylation marks in blood implicate a disease cause, which may affect schizophrenia through processes that are unrelated to methylation in brain. In the ‘mirror site model’ a causal role of methylation sites in brain is assumed. When the methylation status of these sites in brain is mirrored by the corresponding sites in blood, we will observe associations between schizophrenia and methylation marks at the same loci in blood. Compared with tissue-specific differentially methylated regions (T-DMRs) [11] , correlated methylation profiles across tissues are common [12] . Mirror sites occur because peripheral tissues may reveal methylation marks predating or resulting from the epigenetic reprogramming events affecting the germline [13] and embryogenesis [14] , and environmental factors [15] and genetic polymorphisms can affect methylation levels in multiple tissues [16] . One possible explanation for relatively high blood–brain concordance may be that not all methylation marks may have functional consequences. This is different from, for example, gene expression or proteomics studies that by nature reflect function. Methylomic approaches for biomarker discovery The methylation research field is rapidly developing and, similar to genetic studies, there are numerous approaches that can be used. As the knowledge needed to identify good candidate methylation sites is generally lacking, it is important to cover as many methylation sites as possible when performing MWAS. Therefore, biomarker discovery requires an approach that can screen (close to) all approximately 27 million CpGs in the human
610
Biomarkers Med. (2014) 8(5)
genome for their association with the phenotype. Whole genome bisulfite sequencing has the ability to provide extensive coverage both in the context of CpG and of methylated cytosine not followed by guanine, but the method is still too costly to be applied with the large sample sizes needed to obtain sufficient statistical power in MWAS. The use of predesigned methylation arrays is economically feasible in large samples but their coverage is often limited, typically only up to half a million sites (
Could monitoring methylation markers aid the management of schizophrenia? “The unique properties of DNA methylation in combination with rapidly developing laboratory technologies position methylomics research as a particularly promising biomarker platform in the near future.” Keywords: biomarkers • DNA methylation • MBD-seq • methylome-wide association study • MWAS • schizophrenia
Schizophrenia Schizophrenia is a devastating psychiatric condition [1] . Its median lifetime prevalence is 0.7–0.8%. Patients experience hallucinations and delusion as well as impairment in both basic sensory processing and higher cognitive function such as reasoning and planning [2] . Onset is typically in adolescence/early adulthood and the course of illness is characterized by exacerbations, remissions and relapses. Schizophrenia is typically diagnosed using the Diagnostic and Statistical Manual of Mental Disorders (DSM) or the International Classification of Disease (ICD). However, rather than being a single disease entity, it may be a set of several disorders sharing clinical features but having (partly) different underlying causes [3] . These subtypes may be distinguishable from each other with respect to prognosis, course or treatment response. Although the available schizophrenia pharmacotherapies often lack efficacy and/or cause side effects in a substantial group of patients, few new drugs are under development [4] . Therefore, the ability to use biomarkers to better diagnose and optimize existing treatments would be of tremendous clinical value. DNA methylation Epigenetic modifications refer to changes in the DNA that do not involve the nucleotide sequence. One of the most intensively studied modifications is the methylation of DNA cytosine residues at the carbon 5 position. In human (non-stem cell) DNA, this epigenetic mark is mainly found in the sequence context
10.2217/BMM.14.44 © 2014 Future Medicine Ltd
of CpG. DNA methylation can directly affect gene regulation. It is essential for normal cell functioning, and is playing an important role in, for example, brain development [5] . Indeed, aberrant methylation has been associated with a variety of human diseases, including psychiatric conditions [6–8] . Methylation sites as biomarkers Methylation studies particularly offer promise to improve schizophrenia disease management. First, methylation markers may have better predictive power than genetic markers as methylation can directly affect gene regulation. Second, methylation studies may improve disease understanding as they can potentially account for a wide range of clinical features of schizophrenia such as individual differences in course and episodicity. Third, methylation marks are potential drug targets as they are modifiable by pharma ceutical interventions. Finally, as these marks are stable in collected biomaterial, and can be measured cost-effectively in biosamples that are easy to collect such as blood, they are well suited for eventual use in the clinical setting. Concrete examples of potential use include: • Diagnosis: different disease causes may leave different methylation signatures. Methylation marks could therefore potentially help to diagnose etiologically distinct subtypes; • Treatment: methylation as a (early) marker of treatment response can be used to personalize and optimize pharmacotherapy;
Biomarkers Med. (2014) 8(5), 607–611
Karolina A Aberg Author for correspondence: Center for Biomarker Research & Personalized Medicine, Virginia Commonwealth University, VA 23298, USA Tel.: +1 804 628 3023 Fax: +1 804 628 3991 kaaberg@ vcu.edu
Edwin JCG van den Oord Center for Biomarker Research & Personalized Medicine, Virginia Commonwealth University, VA 23298, USA
part of
ISSN 1752-0363
609
Editorial Aberg & van den Oord • Prognosis: an accumulation of evidence from animal and human research demonstrates that alterations in methylation can be persistent over time and have long-term phenotypic consequences [9] . Methylation could therefore predict risks of specific symptom developments and chronicity of the disease. Methylation biomarkers in blood The pathogenic processes for psychiatric disorders likely involve the brain. Although it is advantageous to investigate a methylation mark directly in the most relevant tissue, procurement of brain tissue is typically not possible. Given that blood is easy to collect, with very limited risk to the patient, it is an appealing alternative tissue. There are two models explaining how methylation marks in blood could yield useful biomarkers [10] . It should be noted that neither model assumes that methylation in blood directly affects disease susceptibility. In the ‘signature model’ associations between schizophrenia and methylation marks occur because factors that increase disease susceptibility leave a biomarker signature in blood. Thus, the methylation marks in blood implicate a disease cause, which may affect schizophrenia through processes that are unrelated to methylation in brain. In the ‘mirror site model’ a causal role of methylation sites in brain is assumed. When the methylation status of these sites in brain is mirrored by the corresponding sites in blood, we will observe associations between schizophrenia and methylation marks at the same loci in blood. Compared with tissue-specific differentially methylated regions (T-DMRs) [11] , correlated methylation profiles across tissues are common [12] . Mirror sites occur because peripheral tissues may reveal methylation marks predating or resulting from the epigenetic reprogramming events affecting the germline [13] and embryogenesis [14] , and environmental factors [15] and genetic polymorphisms can affect methylation levels in multiple tissues [16] . One possible explanation for relatively high blood–brain concordance may be that not all methylation marks may have functional consequences. This is different from, for example, gene expression or proteomics studies that by nature reflect function. Methylomic approaches for biomarker discovery The methylation research field is rapidly developing and, similar to genetic studies, there are numerous approaches that can be used. As the knowledge needed to identify good candidate methylation sites is generally lacking, it is important to cover as many methylation sites as possible when performing MWAS. Therefore, biomarker discovery requires an approach that can screen (close to) all approximately 27 million CpGs in the human
610
Biomarkers Med. (2014) 8(5)
genome for their association with the phenotype. Whole genome bisulfite sequencing has the ability to provide extensive coverage both in the context of CpG and of methylated cytosine not followed by guanine, but the method is still too costly to be applied with the large sample sizes needed to obtain sufficient statistical power in MWAS. The use of predesigned methylation arrays is economically feasible in large samples but their coverage is often limited, typically only up to half a million sites (
