Abstract
Depression is currently the leading cause of disability around the world. We conducted an epigenome-wide association study (EWAS) in a sample of 58 depression score-discordant monozygotic ...twin pairs, aiming to detect specific epigenetic variants potentially related to depression and further integrate with gene expression profile data. Association between the methylation level of each CpG site and depression score was tested by applying a linear mixed effect model. Weighted gene co-expression network analysis (WGCNA) was performed for gene expression data. The association of DNA methylation levels of 66 CpG sites with depression score reached the level of
P
< 1 × 10
−4
. These top CpG sites were located at 34 genes, especially
PTPRN2
,
HES5
,
GATA2
,
PRDM7
, and
KCNIP1
. Many ontology enrichments were highlighted, including Notch signaling pathway, Huntington disease, p53 pathway by glucose deprivation, hedgehog signaling pathway, DNA binding, and nucleic acid metabolic process. We detected 19 differentially methylated regions (DMRs), some of which were located at
GRIK2
,
DGKA
, and
NIPA2
. While integrating with gene expression data,
HELZ2
,
PTPRN2
,
GATA2
, and
ZNF624
were differentially expressed. In WGCNA, one specific module was positively correlated with depression score (
r
= 0.62,
P
= 0.002). Some common genes (including
BMP2
,
PRDM7
,
KCNIP1
, and
GRIK2
) and enrichment terms (including complement and coagulation cascades pathway, DNA binding, neuron fate specification, glial cell differentiation, and thyroid gland development) were both identified in methylation analysis and WGCNA. Our study identifies specific epigenetic variations which are significantly involved in regions, functional genes, biological function, and pathways that mediate depression disorder.
Mosaicism in blood varies with age, and cross-sectional studies indicate that for women, skewness of X-chromosomal mosaicism increases with age. This pattern could, however, also be due to less ...X-inactivation in more recent birth cohorts. Skewed X-chromosome inactivation was here measured longitudinally by the HUMARA assay in 67 septuagenarian and octogenarian women assessed at 2 time points, 10 years apart, and in 10 centenarian women assessed at 2 time points, 2-7 years apart. Skewed X-chromosome inactivation was also compared in 293 age-matched septuagenarian twins born in 1917-1923 and 1931-1937, and 212 centenarians born in 1895, 1905 and 1915. The longitudinal study of septuagenarians and octogenarians revealed that 16% (95% CI 7-29%) of the women developed skewed X-inactivation over a 10-year period. In the cross-sectional across-birth cohort study, the earlier-born septuagenarian (1917-1923) and centenarian women (1895) had a higher degree of skewness than the respective recent age-matched birth cohorts, which indicates that the women in the more recent cohorts, after the age of 70, had not only changed degree of skewness with age, they had also undergone less age-related hematopoietic sub-clone expansion. This may be a result of improved living conditions and better medical treatment in the more recent birth cohorts.
Expression of
HOX transcript antisense intergenic
RNA (
HOTAIR
)—a long non-coding RNA—has been examined in a variety of human cancers, and overexpression of
HOTAIR
is correlated with poor survival ...among breast, colon, and liver cancer patients. In this retrospective study, we examine
HOTAIR
expression in 164 primary breast tumors, from patients who do not receive adjuvant treatment, in a design that is paired with respect to the traditional prognostic markers. We show that
HOTAIR
expression differs between patients with or without a metastatic endpoint, respectively. Survival analysis shows that high
HOTAIR
expression in primary tumors is significantly associated with worse prognosis independent of prognostic markers (
P
= 0.012, hazard ratio (HR) 1.747). This association is even stronger when looking only at estrogen receptor (ER)-positive tumor samples (
P
= 0.0086, HR 1.985). In ER-negative tumor samples, we are not able to detect a prognostic value of
HOTAIR
expression, probably due to the limited sample size. These results are successfully validated in an independent dataset with similar associations (
P
= 0.018, HR 1.825). In conclusion, our findings suggest that
HOTAIR
expression may serve as an independent biomarker for the prediction of the risk of metastasis in ER-positive breast cancer patients.
Body mass index (BMI) serves as an important measurement of obesity and adiposity, which are highly correlated with cardiometabolic diseases. Although high heritability has been estimated, the ...identified genetic variants by genetic association studies only explain a small proportion of BMI variation. As an active effort for further exploring the molecular basis of BMI variation, large-scale epigenome-wide association studies have been conducted but with limited number of loci reported, perhaps due to poorly controlled confounding factors, including genetic factors. Being genetically identical, monozygotic twins discordant for BMI are ideal subjects for analyzing the epigenetic association between DNA methylation and BMI, providing perfect control on their genetic makeups largely responsible for BMI variation.
We performed an epigenome-wide association study on BMI using 30 identical twin pairs (15 male and 15 female pairs) with age ranging from 39 to 72 years and degree of BMI discordance ranging from 3-7.5 kg/m
. Methylation data from whole blood samples were collected using the reduced representation bisulfite sequencing technique.
After adjusting for blood cell composition and clinical variables, we identified 136 CpGs with p-value < 1e-4, 30 CpGs with p < 1e-05 but no CpGs reached genome-wide significance. Genomic region-based analysis found 11 differentially methylated regions harboring coding and non-coding genes some of which were validated by gene expression analysis on independent samples.
Our DNA methylation sequencing analysis on identical twins provides new references for the epigenetic regulation on BMI and obesity.
The therapeutic management of obesity is challenging, hence further elucidating the underlying mechanisms of obesity development and identifying new diagnostic biomarkers and therapeutic targets are ...urgent and necessary. Here, we performed differential gene expression analysis and weighted gene co-expression network analysis (WGCNA) to identify significant genes and specific modules related to BMI based on gene expression profile data of 7 discordant monozygotic twins.
In the differential gene expression analysis, it appeared that 32 differentially expressed genes (DEGs) were with a trend of up-regulation in twins with higher BMI when compared to their siblings. Categories of positive regulation of nitric-oxide synthase biosynthetic process, positive regulation of NF-kappa B import into nucleus, and peroxidase activity were significantly enriched within GO database and NF-kappa B signaling pathway within KEGG database. DEGs of NAMPT, TLR9, PTGS2, HBD, and PCSK1N might be associated with obesity. In the WGCNA, among the total 20 distinct co-expression modules identified, coral1 module (68 genes) had the strongest positive correlation with BMI (r = 0.56, P = 0.04) and disease status (r = 0.56, P = 0.04). Categories of positive regulation of phospholipase activity, high-density lipoprotein particle clearance, chylomicron remnant clearance, reverse cholesterol transport, intermediate-density lipoprotein particle, chylomicron, low-density lipoprotein particle, very-low-density lipoprotein particle, voltage-gated potassium channel complex, cholesterol transporter activity, and neuropeptide hormone activity were significantly enriched within GO database for this module. And alcoholism and cell adhesion molecules pathways were significantly enriched within KEGG database. Several hub genes, such as GAL, ASB9, NPPB, TBX2, IL17C, APOE, ABCG4, and APOC2 were also identified. The module eigengene of saddlebrown module (212 genes) was also significantly correlated with BMI (r = 0.56, P = 0.04), and hub genes of KCNN1 and AQP10 were differentially expressed.
We identified significant genes and specific modules potentially related to BMI based on the gene expression profile data of monozygotic twins. The findings may help further elucidate the underlying mechanisms of obesity development and provide novel insights to research potential gene biomarkers and signaling pathways for obesity treatment. Further analysis and validation of the findings reported here are important and necessary when more sample size is acquired.
We analyzed data from twins to determine how much the familial risk of colorectal cancer can be attributed to genetic factors vs environment. We also examined whether heritability is distinct for ...colon vs rectal cancer, given evidence of distinct etiologies.
Our data set included 39,990 monozygotic and 61,443 same-sex dizygotic twins from the Nordic Twin Study of Cancer. We compared each cancer's risk in twins of affected co-twins relative to the cohort risk (familial risk ratio FRR). We then estimated the proportion of variation in risk that could be attributed to genetic factors (heritability).
From earliest registration in 1943 through 2010, there were 1861 individuals diagnosed with colon cancer and 1268 diagnosed with rectal cancer. Monozygotic twins of affected co-twins had an FRR for colorectal cancer of 3.1 (95% confidence interval CI, 2.4-3.8) relative to the cohort risk. Dizygotic twins of affected co-twins had an FRR for colorectal cancer of 2.2 (95% CI, 1.7-2.7). We estimated that 40% (95% CI, 33%-48%) of the variation in colorectal cancer risk could be attributed to genetic factors; unique environment only accounted for the remaining liability. For colon cancer, the FRR was 3.3 (95% CI, 2.1-4.5) for monozygotic twins and 2.6 (95% CI, 1.7-3.5) for dizygotic twins. For rectal cancer, comparable estimates were 3.3 (95% CI, 1.5-5.1) for monozygotic twins and 2.6 (95% CI, 1.2-4.0) for dizygotic twins. Heritability estimates for colon and rectal cancer were 16% (95% CI, 0-46%) and 15% (95% CI, 0-50%), common environment estimates were 15% (95% CI, 0-38%) and 11% (95% CI, 0-38%), and unique environment estimates were 68% (95% CI, 57%-79%) and 75% (95% CI, 61%-88%), respectively.
Interindividual genetic differences could account for 40% of the variation in susceptibility to colorectal cancer; risk for colon and rectal cancers might have less of a genetic component than risk for colorectal cancer. Siblings, and particularly monozygotic co-twins, of individuals with colon or rectal cancer should consider personalized screening.
•The epigenome of identical twins can serve as a perfect laboratory for studying the environmental impact on behavioral traits.•The discordant twin design is a powerful tool for epigenetic ...association study.•The use of the design in linking specific environmental exposures with epigenetic modification should be encouraged.•Twins are useful for causal inference in behavioral epigenetics for finding effective biomarkers as targets for intervention and prevention.
The debate upon the relative importance of nature vs nurture in the development of human behaviour can be traced back to ancient times. Traditional epidemiology and genetic epidemiology have confirmed the association of environmental and genetic factors with behavioural traits. Current genomic studies are identifying genetic variants associated with various behavioural traits. However, exploring the relationship of abundant environmental factors with the complex epigenome that mediates human behaviour is just at its beginning. Identical twins can serve as perfect experiments for studying the environmental impact on behavioural epigenetics advantaged by enriched power in association analysis due to controlling of their genetic make-ups. Recent development in causal inference using twin-based models adds more values in twins. This review briefly introduces the various approaches in making use of twins in studying behavioural epigenetics from experiment design to practical applications. Exploring the epigenome of twins using the powerful twin-based study designs and analytical approaches will help identifying causal epigenetic markers mediating environmental exposures and behavioural traits enabling both pharmaceutical intervention and effective prevention.
Abstract Background Cardiovascular diseases (CVDs) are major causes of mortality and morbidity worldwide; yet the understanding of their molecular basis is incomplete. Multi-omics studies have ...significant potential to uncover these mechanisms, but such studies are challenged by genetic and environmental confounding—a problem that can be effectively reduced by investigating intrapair differences in twins. Here, we linked data on all diagnoses of the circulatory system from the nationwide Danish Patient Registry (spanning 1977–2022) to a study population of 835 twins holding genome-wide DNA methylation and gene expression data. CVD diagnoses were divided into prevalent or incident cases (i.e., occurring before or after blood sample collection (2007–2011)). The diagnoses were classified into four groups: cerebrovascular diseases, coronary artery disease (CAD), arterial and other cardiovascular diseases (AOCDs), and diseases of the veins and lymphatic system. Statistical analyses were performed by linear (prevalent cases) or cox (incident cases) regression analyses at both the individual-level and twin pair-level. Significant genes ( p < 0.05) in both types of biological data and at both levels were inspected by bioinformatic analyses, including gene set enrichment analysis and interaction network analysis. Results In general, more genes were found for prevalent than for incident cases, and bioinformatic analyses primarily found pathways of the immune system, signal transduction and diseases for prevalent cases, and pathways of cell–cell communication, metabolisms of proteins and RNA, gene expression, and chromatin organization groups for incident cases. This potentially reflects biology related to response to CVD (prevalent cases) and mechanisms related to regulation and development of disease (incident cases). Of specific genes, Myosin 1E was found to be central for CAD, and DEAD-Box Helicase 5 for AOCD. These genes were observed in both the prevalent and the incident analyses, potentially reflecting that their DNA methylation and gene transcription levels change both because of disease (prevalent cases) and prior disease (incident cases). Conclusion We present novel biomarkers for CVD by performing multi-omics analysis in twins, hereby lowering the confounding due to shared genetics and early life environment—a study design that is surprisingly rare in the field of CVD, and where additional studies are highly needed.
Semantic fluency impairment has been attributed to a wide range of neurocognitive and psychiatric conditions, especially in the older population. Moderate heritability estimates on semantic fluency ...were obtained from both twin and family-based studies suggesting genetic contributions to the observed variation across individuals. Currently, effort in identifying the genetic variants underlying the heritability estimates for this complex trait remains scarce. Using the semantic fluency scale and genome-wide SNP genotype data from the Long Life Family Study (LLFS), we performed a genome-wide association study (GWAS) and epistasis network analysis on semantic fluency in 2289 individuals aged over 60 years from the American LLFS cohorts and replicated the findings in 1129 individuals aged over 50 years from the Danish LLFS cohort. In the GWAS, two SNPs with genome-wide significance (rs3749683,
= 2.52 × 10
; rs880179,
= 4.83 × 10
) mapped to the
gene on chromosome 5 were detected. The epistasis network analysis identified five modules as significant (4.16 × 10
<
< 7.35 × 10
), of which two were replicated (
< 3.10 × 10
). These two modules revealed significant enrichment of tissue-specific gene expression in brain tissues and high enrichment of GWAS catalog traits, e.g., obesity-related traits, blood pressure, chronotype, sleep duration, and brain structure, that have been reported to associate with verbal performance in epidemiological studies. Our results suggest high tissue specificity of genetic regulation of gene expression in brain tissues with epistatic SNP networks functioning jointly in modifying individual verbal ability and cognitive performance.
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