Genetic vulnerability to DUSP22 promoter hypermethylation is involved in the relation between in utero famine exposure and schizophrenia

Boks, Marco P.; Houtepen, Lotte C; Xu, Zhida; He, Yujie; Ursini, Gianluca; Maihofer, Adam X.; Rajarajan, Prashanth; Yu, Qiong; Xu, Hao; Wu, Ying; Wang, S; Shi, Jieping; Pol, Hilleke E. Hulshoff; Strengman, Eric; Rutten, Bart P. F.; Jaffe, Andrew E.; Kleinman, Joel E.; Baker, Dewleen G.; Hol, Elly M.; Akbarian, Schahram; Nievergelt, Caroline M.; Witte, Lot de; Vinkers, Christiaan H.; Weinberger, Daniel R.; Yu, Jinghai; Kahn, René S.

doi:10.1038/s41537-018-0058-4

Cited by 41 publications

(40 citation statements)

References 51 publications

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“…Another factor that could influence gene transcription level are genetic variants. For instance, gene polymorphism of FKBP5 , an important functional regulator of the glucocorticoid receptor (GR), can mediated gene–childhood trauma interactions through DNA methylation level (32) and similarly genetic variants modify the methylation response to maternal famine (33). The KITLG locus in the current study contains just one genetic variant with no functional relevance for expression and therefore no indication of a role in genetic regulation is currently available.…”

Section: Discussionmentioning

confidence: 99%

Childhood Adversity Is Associated With Increased KITLG Methylation in Healthy Individuals but Not in Bipolar Disorder Patients

Vinkers

Houtepen

et al. 2019

Front. Psychiatry

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Background: Childhood adversity increases the risk of a range of mental disorders including bipolar disorder, but the underlying mechanisms are still unknown. Previous studies identified DNA methylation levels at the cg27512205 locus on the KIT Ligand (KITLG) gene as a mediator between childhood adversity and stress responsivity. This raises the question whether this locus also plays a role in stress related disorders such as bipolar disorder. Therefore, the current study aims to compare the level of KITLG (cg27512205) methylation between bipolar patients and healthy individuals and its relation to childhood adversity.Methods: KITLG (cg27512205) methylation was measured in 50 bipolar disorder patients and 91 healthy control participants using the HumanMethylation450K BeadChip platform. Childhood adversity in each individual was assessed using the Childhood Trauma Questionnaire. Analyses of the association of KITLG methylation with bipolar disorder, the association of childhood adversity with bipolar disorder as well as the association of KITLG methylation with childhood adversity in bipolar patients and controls were conducted using linear regression with age, gender, childhood adversity, smoking, and cell-type composition estimates as covariates.Results: KITLG (cg27512205) methylation level was significantly lower in bipolar disorder patients (β = −0.351, t = −6.316 p < 0.001). Childhood adversity levels were significantly higher in the bipolar disorder group (β = 4.903, t = 2.99, p = 0.003). In the bipolar disorder patients KITLG methylation was not associated with childhood adversity (β = 0.004, t = 1.039, p = 0.304) in contrast to the healthy controls (β = 0.012, t = 3.15, p = 0.002).Conclusions: KITLG methylation was lower in bipolar disorder despite high levels of childhood adversity, whereas childhood adversity was associated with higher KITLG methylation in healthy controls. In addition to lower methylation at this locus there is an indication that failure to adjust KITLG methylation to high levels of childhood adversity is a risk factor for bipolar disorder.

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Section: Discussionmentioning

confidence: 99%

Childhood Adversity Is Associated With Increased KITLG Methylation in Healthy Individuals but Not in Bipolar Disorder Patients

Vinkers

Houtepen

et al. 2019

Front. Psychiatry

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“…Hence, it is significant to conduct a follow-up study in the future for more comprehensive data. The last limitation is that the CpGs for the mediation-analysis were found only in our Suihua cohort, but some of these differentially methylated sites have been reported in previous famine studies using the Illumina 450k arrays [ 36 – 38 ], such as those located in solute carrier family 38 member 2 (SLC38A2), phospholipid phosphatase 2 (PPAP2C), zinc finger protein 385A (ZNF385A) and family with sequence similarity 150 member B (FAM150B). These consistent observations further demonstrated the impact of famine on the epigenetic changes.…”

Section: Discussionmentioning

confidence: 99%

Prenatal famine exposure and estimated glomerular filtration rate across consecutive generations: association and epigenetic mediation in a population-based cohort study in Suihua China

Jiang

Han

Duan

et al. 2020

Aging

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Prenatal malnutrition could promote renal dysfunction in adulthood, but it is unclear whether the detrimental effect could be transmitted to the next generation. We investigated whether famine exposure was associated with variation of estimated glomerular filtration rate(eGFR) in two generations and explored the mediation role of methylation alterations. The longitudinal analysis included 2909 participants from Suihua rural area. F1 and F2 generations were divided into non-famine and famine group based on their birth year and exposure status of their parents, respectively. The eGFR was calculated by using the chronic kidney disease epidemiology collaboration equation. We applied mixed-effect models to investigate the association between famine and ΔeGFR and tested blood DNA methylomes in 46 families across two generations. The mediation-analysis models were utilized to examine the mediation effect of methylation alterations on the famine-ΔeGFR association. In mixed-effect models, famine exposure was associated with declined ΔeGFR level in F1 (β:-8.32;95%CI:-11.51,-5.12) and in F2 (β:-6.11;95%CI:-11.88,-0.43). Methylation850K BeadChip data showed only 19 of 961 F1 differentially methylated sites showed concordant alterations in F2. The mediation-analysis results showed methylation alterations on AGTR1 and PRKCA might mediate the famine-ΔeGFR association. Overall, prenatal famine exposure may have long-term effects on eGFR decline across consecutive generations which might be partly mediated by methylation alterations on AGTR1 and PRKCA.

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“…The sample of Chinese famine is part of our previous study and has been described in more detail elsewhere [9]. In short, volunteers were recruited in the northern province of Jilin, China.…”

Section: Methodsmentioning

confidence: 99%

“…Subsequent studies of this cohort identified DNA methylation changes as mediators of the association between maternal famine and metabolic disease in adulthood [6, 8]. Other epigenetic differences associated with famine exposure in utero have been related to schizophrenia [9] and type 2 diabetes [10].…”

Section: Introductionmentioning

confidence: 99%

“…Studies also showed a twofold increased risk to develop schizophrenia among offspring conceived at the height of the famine [15, 16]. However, only one genome-wide DNA methylation study is reported in the Chinese famine population [17]. To further understand the impact of maternal famine on DNA methylation changes in offspring, we compared genome-wide DNA methylation from whole blood of Chinese participants exposed to famine in the first trimester to unexposed controls from the same populations.…”

Section: Introductionmentioning

confidence: 99%

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DNA methylation changes related to nutritional deprivation: a genome-wide analysis of population and in vitro data

Witte

Houtepen

et al. 2019

Clin Epigenet

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Background DNA methylation has recently been identified as a mediator between in utero famine exposure and a range of metabolic and psychiatric traits. However, genome-wide analyses are scarce and cross-sectional analyses are hampered by many potential confounding factors. Moreover, causal relations are hard to identify due to the lack of controlled experimental designs. In the current study, we therefore combined a comprehensive assessment of genome-wide DNA methylation differences in people exposed to the great Chinese famine in utero with an in vitro study in which we deprived fibroblasts of nutrition. Methods We compared whole blood DNA methylation differences between 25 individuals in utero exposed to famine and 54 healthy control individuals using the HumanMethylation450 platform. In vitro, we analyzed DNA methylation changes in 10 fibroblast cultures that were nutritionally deprived for 72 h by withholding fetal bovine serum. Results We identified three differentially methylated regions (DMRs) in four genes ( ENO2 , ZNF226 , CCDC51 , and TMA7 ) that were related to famine exposure in both analyses. Pathway analysis with data from both Chinese famine samples and fibroblasts highlighted the nervous system and neurogenesis pathways as the most affected by nutritional deprivation. Conclusions The combination of cross-sectional and experimental data provides indications that biological adaptation to famine leads to DNA methylation changes in genes involved in the central nervous system. Electronic supplementary material The online version of this article (10.1186/s13148-019-0680-7) contains supplementary material, which is available to authorized users.

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Genetic vulnerability to DUSP22 promoter hypermethylation is involved in the relation between in utero famine exposure and schizophrenia

Cited by 41 publications

References 51 publications

Childhood Adversity Is Associated With Increased KITLG Methylation in Healthy Individuals but Not in Bipolar Disorder Patients

Childhood Adversity Is Associated With Increased KITLG Methylation in Healthy Individuals but Not in Bipolar Disorder Patients

Prenatal famine exposure and estimated glomerular filtration rate across consecutive generations: association and epigenetic mediation in a population-based cohort study in Suihua China

DNA methylation changes related to nutritional deprivation: a genome-wide analysis of population and in vitro data

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