DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases

Ligthart, Symen; Marzi, Carola; Aslibekyan, Stella; Mendelson, Michael; Conneely, Karen N.; Tanaka, Toshiko; Colicino, Elena; Waite, Lindsay L.; Joehanes, Roby; Guan, Weihua; Brody, Jennifer A.; Elks, Cathy E.; Marioni, Riccardo E.; Jhun, Min A.; Agha, Golareh; Bressler, Jan; Ward‐Caviness, Cavin; Chen, Brian H.; Huan, Tianxiao; Bakulski, Kelly M.; Salfati, Elias; Fiorito, Giovanni; Wahl, Simone; Schramm, Katharina; Jiang, Sha; Hernandez, Dena G.; Just, Allan C.; Smith, Jennifer A.; Sotoodehnia, Nona; Pilling, Luke C.; Pankow, James S.; Tsao, Phil; Liu, Chunyu; Zhao, Wei; Guarrera, Simonetta; Michopoulos, Vasiliki; Smith, Alicia K.; Peters, Marjolein J.; Melzer, David; Vokonas, Pantel; Fornage, Myriam; Prokisch, Holger; Bis, Joshua C.; Chu, Audrey Y.; Herder, Christian; Grallert, Harald; Yao, Chen; Shah, Sonia; McRae, Allan F.; Lin, Honghuang; Horvath, Steve; Fallin, Danièle; Hofman, Albert; Wareham, Nicholas J.; Wiggins, Kerri L.; Feinberg, Andrew P.; Starr, John M.; Visscher, Peter M.; Murabito, Joanne M.; Kardia, Sharon L.R.; Absher, Devin; Binder, Elisabeth B.; Singleton, Andrew B.; Bandinelli, Stefania; Peters, Annette; Waldenberger, Mélanie; Matullo, Giuseppe; Schwartz, Joel; Demerath, Ellen W.; Uitterlinden, André G.; Meurs, Joyce B. J. van; Franco, Oscar H.; Chen, Yii‐Der Ida; Levy, Daniel; Turner, Stephen T.; Deary, Ian J.; Ressler, Kerry J.; Dupuis, Josée; Ferrucci, Luigi; Ong, Ken K.; Assimes, Themistocles L.; Boerwinkle, Eric; Köenig, Wolfgang; Arnett, Donna K.; Baccarelli, Andrea A.; Benjamin, Emelia J.; Dehghan, Abbas

doi:10.1186/s13059-016-1119-5

Cited by 265 publications

(307 citation statements)

References 29 publications

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“…Blood is a primary tissue for research focussed on immune response and peripheral inflammation [16, 17]. Indeed, a wide range of psychiatric disorders have been associated with peripheral inflammation and altered immune response [18].…”

Section: Discussionmentioning

confidence: 99%

Epigenetics, Early Adversity and Child and Adolescent Mental Health

Barker¹

2018

Psychopathology

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Epigenetic modification, such as DNA methylation (DNAm), is a mechanism that can help explain how early adversities can engender long-term vulnerability for mental health problems. At present, there is preliminary evidence to support the possibility of epigenetic mediation: environmental factors are reported to influence offspring DNAm, which in turn associate with child and adolescent psychopathology. However, all analyses have been correlational in nature and, as these studies have focussed on children and adolescents, DNAm has been based on peripheral tissue (cord blood, whole blood, buccal cells). Therefore, the extent to which DNAm could represent a causal mechanism (e.g., a surrogate of central nervous system function) or a biomarker (i.e., an indicator of the pathological process leading to disease) is unclear. This short report has 2 main components. First, 2 studies are summarized, one a candidate gene study and the other an epigenome-wide association study in which DNAm was reported to (partially) mediate the link between adversity and child development. Second, there is a discussion of (1) the “tissue issue,” (2) maximizing the interpretability of candidate gene and epigenome-wide approaches, and (3) the need for examining DNAm as a potential biomarker for mental health. It is argued that advances within these 3 areas will make clearer the role of DNAm in the link between adversity and child and adolescent mental health.

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Section: Discussionmentioning

confidence: 99%

Epigenetics, Early Adversity and Child and Adolescent Mental Health

Barker¹

2018

Psychopathology

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“…They vary across individuals and this variation has been robustly associated with a range of disease phenotypes and environmental exposures [1][2][3][4][5][6]. As interindividual DNA methylation is specified by the interaction of both genotypic and environmental influences [7,8], it may be a more powerful prognostic biomarker than either genotypic or lifestyle factors alone [9].…”

Section: Dna Methylation Marks Integrate Genetic and Environmental Inflmentioning

confidence: 99%

Is Cellular Heterogeneity Merely a Confounder to be Removed from Epigenome-Wide Association Studies?

et al. 2017

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Excitement about DNA methylation biomarkers has been tempered by a growing appreciation of the complex causal relations with cell fate. Intersample differences in DNA methylation can be partitioned into those that are independent of cellular heterogeneity and those that are caused by differential mixtures of cell types. Generally, the field has assumed that the former are more likely to be causative of disease. The latter has been considered a likely consequence of disease and a confounder to be removed. We argue that the conceptual separation of these signals is artificial and not necessarily informative about causation. DNA methylation is a very sensitive measure of cell fate mix and therefore reveals much about underlying disease etiology including aspects of causation. DNA methylation marks integrate genetic & environmental influences & hence have potential as prognostic & stratification biomarkers & also as read-outs of intervention efficacyLoci-specific DNA 5-methylcytosine levels at CpG sites are easily measured at scale in biological samples. They vary across individuals and this variation has been robustly associated with a range of disease phenotypes and environmental exposures [1][2][3][4][5][6]. As interindividual DNA methylation is specified by the interaction of both genotypic and environmental influences [7,8], it may be a more powerful prognostic biomarker than either genotypic or lifestyle factors alone [9]. DNA methylation is dynamic throughout the lifecourse and is potentially modifiable by therapeutic interventions. This raises the possibility of sensitive real-time biomarkers of disease status to track intervention efficacy [10].Locus-specific observations were first to demonstrate the role of early life environmental influence on interindividual variation in methylation. For instance, postnatal maternal care in rats or childhood trauma in humans, affects DNA methylation levels at the NR3C1 gene in blood and the hippocampus; methylation levels at this locus then predict adult psychopathology [11][12][13]. Observations such as this have inspired many epigenome wide association studies (EWAS) to determine the epigenetic consequences of early life influences. Although epigenetic programming was originally envisioned to pertain to very early life factors (i.e., fetal programming, see for example [14]), it could be generalized to account for environmental influences throughout the lifecourse. Some of the best evidence for the later life effect of the environment on DNA methylation is from Fasanelli and colleagues, who showed (by EWAS) that smoking reversibly caused hypomethylation of the AHRR and FR2L3 genes in adults and that

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“…On the other hand, low-grade inflammation (demonstrated most notably by laboratory-induced elevations in inflammatory cytokines, such as IL-6 and TNF-α) can itself promote depressive symptoms, anxiety, fatigue, cognitive disruptions, and pain [78]. Moreover, chronic inflammation is associated with epigenetic changes [79], and appears to contribute to most, if not all, NCDs [80].…”

Section: Biophilosophymentioning

confidence: 99%

Down to Earth: Planetary Health and Biophilosophy in the Symbiocene Epoch

Prescott

Logan

2017

Challenges

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Advances in science have illuminated the role of the "ecological theatre"-the total living environment-in human health. In a rapidly changing epoch known as the anthropocene, microbiome science is identifying functional connections between all life, both seen and unseen. Rather than an easily identifiable era appearing in rock strata, the anthropocene is more of a diagnostic syndrome, a set of signs and symptoms including climate change, gross biodiversity losses, environmental degradation, and an epidemic of non-communicable diseases. The syndrome is intertwined with politics, economics, public policies (or lack thereof), social values, and a global push of calorie-dense, nutrient-poor foods and beverages. The healing of anthropocene syndrome is the grand challenge of humanity. Expanding on the "Mars Can Wait" argument of Geoffrey Goodman, et al., we focus on the urgency with which health promotion must be prioritized here on Earth. We revive Jonas Salk's biophilosophy: a call to action for collaboration between biologists, humanists, and scholars of all stripes. From this perspective, lines of distinction between personal, public, and planetary health are removed. We also describe the symbiocene: the possibility of a new epoch in which mutualism will be considered imperative. If society asks the right questions, a transition to the symbiocene is possible; the "stratigraphical" mark of the new epoch will be found in a repudiation of authoritarianism, and the promotion of empathy, cultural competency, emotional intelligence, and commitment to optimism, tolerance, and the facilitation of the WHO definition of health, i.e., the fulfillment of human potential.

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DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases

Cited by 265 publications

References 29 publications

Epigenetics, Early Adversity and Child and Adolescent Mental Health

Epigenetics, Early Adversity and Child and Adolescent Mental Health

Is Cellular Heterogeneity Merely a Confounder to be Removed from Epigenome-Wide Association Studies?

Down to Earth: Planetary Health and Biophilosophy in the Symbiocene Epoch

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