X chromosome inactivation patterns correlate with fetal-placental anatomy in monozygotic twin pairs: implications for immune relatedness and concordance for autoimmunity.

BACKGROUND: Monozygotic (MZ) twinning is a poorly understood phenomenon that may result in subtle biologic differences between twins, despite their identical inheritance. These differences may in part account for discordant expression of disease in MZ twin pairs. Due to their stochastic nature, differences in X chromosome inactivation patterns are one source of such variation in female MZ twins. MATERIALS AND METHODS: We investigated X chromosome inactivation patterns in the blood of 41 MZ twin pairs based on methylation of the androgen receptor gene using a Hpa II-PCR assay. Twenty-six female MZ twin pairs with autoimmune disease (rheumatoid arthritis or multiple sclerosis) were studied. In addition, we studied 15 newborn female MZ twin pairs who were characterized at birth with respect to the anatomy of chorionic membranes (dichorionic versus monochorionic). RESULTS: We found a strong correlation between dichorionic fetal anatomy and differences in X chromosome inactivation patterns between members of an MZ twin pair. In contrast, all monochorionic twin pairs had closely correlated patterns of X chromosome inactivation. X chromosome inactivation patterns did not distinguish between MZ twin pairs who were concordant or discordant for autoimmune disease. CONCLUSIONS: The highly similar patterns of X chromosome inactivation among monochorionic twin pairs may result from their shared placental blood supply during intrauterine life. Alternatively, these patterns may indicate that X chromosome inactivation occurs before the twinning event in this anatomic subgroup of MZ twins. The data further suggest that these factors do not make a major contribution to the high discordance rates for autoimmune disease in MZ twin pairs.     

Commitment to X inactivation precedes the twinning event in monochorionic MZ twins.

To gain insight into the timing of twinning, we have examined a closely related event, X-chromosome inactivation, in female MZ twin pairs. X-inactivation patterns in peripheral blood and buccal mucosa were compared between monochorionic MZ (MC-MZ) and dichorionic MZ (DC-MZ) twins. Overall, the MC-MZ twins displayed highly similar X-inactivation patterns, whereas DC-MZ twins frequently differed in their X-inactivation patterns, when both tissues were tested. Previous experimental data suggest that commitment to X inactivation occurs when there are 10-20 cells in the embryo. Simulation of embryo splitting after commitment to X inactivation suggests that MC-MZ twinning occurs three or four rounds of replication after X inactivation, whereas a DC-MZ twinning event occurs earlier, before or around the time of X inactivation. Finally, the overall degree of skewing in the MZ twins was not significantly different from that observed in singletons. This indicates that X inactivation does not play a direct role in the twinning process, and it further suggests that extreme unequal splitting is not a common mechanism of twin formation.     

Studies of X inactivation and isodisomy in twins provide further evidence that the X chromosome is not involved in Rett syndrome.

Rett syndrome (RS), a progressive encephalopathy with onset in infancy, has been attributed to an X-linked mutation, mainly on the basis of its occurrence almost exclusively in females and its concordance in female MZ twins. The underlying mechanisms proposed are an X-linked dominant mutation with male lethality, uniparental disomy of the X chromosome, and/or some disturbance in the process of X inactivation leading to unequal distributions of cells expressing maternal or paternal alleles (referred to as a "nonrandom" or "skewed" pattern of X inactivation). To determine if the X chromosome is in fact involved in RS, we studied a group of affected females including three pairs of MZ twins, two concordant for RS and one uniquely discordant for RS. Analysis of X-inactivation patterns confirms the frequent nonrandom X inactivation previously observed in MZ twins but indicates that this is independent of RS. Analysis of 29 RS females reveals not one instance of uniparental X disomy, extending the observations previously reported. Therefore, our findings contribute no support for the hypothesis that RS is an X-linked disorder. Furthermore, the concordant phenotype in most MZ female twins with RS, which has not been observed in female twins with known X-linked mutations, argues against an X mutation.     

A longitudinal twin study of skewed X chromosome-inactivation

X-chromosome inactivation (XCI) is a pivotal epigenetic mechanism involved in the dosage compensation of X-linked genes between males and females. In any given cell, the process of XCI in early female development is thought to be random across alleles and clonally maintained once established. Recent studies, however, suggest that XCI might not always be random and that skewed inactivation may become more prevalent with age. The factors influencing such XCI skewing and its changes over time are largely unknown. To elucidate the influence of stochastic, heritable and environmental factors in longitudinal changes in XCI, we examined X inactivation profiles in a sample of monozygotic (MZ) (n = 23) and dizygotic (DZ) (n = 22) female twin-pairs at ages 5 and 10 years. Compared to MZ twins who were highly concordant for allelic XCI ratios, DZ twins showed much lower levels of concordance. Whilst XCI patterns were moderately stable between ages 5 and 10 years, there was some drift over time with an increased prevalence of more extreme XCI skewing at age 10. To our knowledge, this study represents the earliest longitudinal assessment of skewed XCI patterns, and suggests that skewed XCI may already be established in early childhood. Our data also suggest a link between MZ twinning and the establishment of allelic XCI ratios, and demonstrate that acquired skewing in XCI after establishment is primarily mediated by stochastic mechanisms. These data have implications for our understanding about sex differences in complex disease, and the potential causes of phenotypic discordance between MZ female twins.     

Growth patterns in young adult monozygotic twin pairs discordant and concordant for obesity.

Weight discordance is very rare in monozygotic (MZ) twin pairs; when found, however, such pairs are advantageous in the search for either environmental or epigenetic causes and consequences of obesity. We analyzed the growth patterns of young adult MZ pairs discordant and concordant for obesity. Screening 5 consecutive birth cohorts (1975-1979) of 22- to 27-year-old Finnish twins (the FinnTwin16 study), we found 14 obesity discordant (Body Mass Index [BMI] difference > or = 4 kg/m2) MZ pairs out of 658. Ten pairs participated in clinical studies. Nine concordant pairs (BMI difference < or = 2 kg/m2) were examined as controls. Lifetime measured heights and weights recorded in hospitals and health centers were traced manually. Height development was similar in all the co-twins of both groups. The weight differences between the co-twins of the discordant pairs began to emerge at 18 years leading to an average discordance of 16.4 kg, 5.6 kg/m2 (p for both = .005) at 25.7 years. The heavier co-twin weighed 221 g (p = .066), 1.0 kg/m2 (p = .01) more already at birth than the leaner, but the differences waned by 6 months of age and reappeared only after adolescence. Both the leaner and the heavier co-twins of the discordant pairs weighed more than expected by the singleton reference values (Cole et al., 1998) after 8 years. The concordant co-twins, on the other hand, grew similarly and after 6 months, their mean growth was not distinguishable from the singleton patterns. Young adulthood represents a critical period of gaining weight irrespective of genetic background in this twin sample.     

EEG differences in neurotic as compared with normal twin pairs

Summary The resting EEGs of 17 twin pairs originally traced through one neurotic co-twin (10 monozygotic and 7 dizygotic pairs aged between 18 and 63 years) have been described and compared with the neuroticism scores (Schepank, 1974) of these twins. EEG comparison according to the customary visual criteria failed to show any consistent EEG differences between monozygotic co-twins, whereas dizygotic pairs often showed EEG discordance. Computerized time-domain (interval-amplitude) analysis failed to show a higher degree of EEG discordance between neurotic MZ cotwins than between co-twins in 25 adult nonneurotic male MZ pairs (age range 18–33; mean age 22.9 years). There were no significant correlations between EEG differences and differences in the neuroticism score among ten MZ pairs traced through a neurotic co-twin. It is concluded that the individual and genetically determined EEG pattern is manifest even in the face of the long-lasting psychological alterations observed in neurotics.     

Potential bias regarding birth weight in historical and contemporary twin data bases.

In this study we examine the hypothesis that monozygotic (MZ) twins in historical databases are less discordant for birth weight due to negative selection of severely discordant MZ twins. Furthermore, we test the hypothesis that MZ twins are less discordant for birth weight when comparing a volunteer based twin registry with a population based twin registry, due to selective registration. Data were available on 3927 twin pairs from the volunteer Australian Twin Registry born before 1964, 3059 volunteer twin pairs from the Netherlands Twin Register born 1987-1989 and 454 Belgian twin pairs from The East Flanders Prospective Twin Survey born 1987-1989. Intrapair relative birth weight differences (RBWD) were computed for MZ and dizygotic (DZ) twins from each twin registry. Comparing birth weight differences between MZ and DZ twins provides support for the hypothesis that MZ twins are subject to a negative selection in historical databases. Furthermore, Australian MZ twins have a lower RBWD compared to Dutch MZ twins when corrected for the RBWD of Australian and Dutch DZ twins, indicating circumstances which only affect MZ twins. Our hypothesis that MZ twins are less discordant for birth weight in a volunteer based twin registry compared to a population based twin registry had to be rejected. We suggest that investigators using historical databases to test the fetal origins hypothesis should be aware of this increased likelihood of selective exclusion of individuals with extreme morphometric parameters at time of birth.     

Intra-Monozygotic Twin Pair Discordance and Longitudinal Variation of Whole-Genome Scale DNA Methylation in Adults

Monozygotic twins share identical genomic DNA and are indistinguishable using conventional genetic markers. Increasing evidence indicates that monozygotic twins are epigenetically distinct, suggesting that a comparison between DNA methylation patterns might be useful to approach this forensic problem. However, the extent of epigenetic discordance between healthy adult monozygotic twins and the stability of CpG loci within the same individual over a short time span at the whole-genome scale are not well understood. Here, we used Infinium HumanMethylation450 Beadchips to compare DNA methylation profiles using blood collected from 10 pairs of monozygotic twins and 8 individuals sampled at 0, 3, 6, and 9 months. Using an effective and unbiased method for calling differentially methylated (DM) CpG sites, we showed that 0.087%–1.530% of the CpG sites exhibit differential methylation in monozygotic twin pairs. We further demonstrated that, on whole-genome level, there has been no significant epigenetic drift within the same individuals for up to 9 months, including one monozygotic twin pair. However, we did identify a subset of CpG sites that vary in DNA methylation over the 9-month period. The magnitude of the intra-pair or longitudinal methylation discordance of the CpG sites inside the CpG islands is greater than those outside the CpG islands. The CpG sites located on shores appear to be more suitable for distinguishing between MZ twins.     

Asymmetries of the Arcuate Fasciculus in Monozygotic Twins: Genetic and Nongenetic Influences

We assessed cerebral asymmetry for language in 35 monozygotic twin pairs. Using DTI, we reconstructed the arcuate fasciculus in each twin. Among the male twins, right-handed pairs showed greater left-sided asymmetry of connectivity in the arcuate fasciculus than did those with discordant handedness, and within the discordant group the right-handers had greater left-sided volume asymmetry of the arcuate fasciculus than did their left-handed co-twins. There were no such effects in the female twins. Cerebral asymmetry for language showed more consistent results, with the more left-cerebrally dominant twins also showing more leftward asymmetry of high anisotropic fibers in the arcuate fasciculus, a result applying equally to female as to male twins. Reversals of arcuate fasciculus asymmetry were restricted to pairs discordant for language dominance, with the left-cerebrally dominant twins showing leftward and the right-cerebrally dominant twins rightward asymmetry of anisotropic diffusion in the arcuate fasciculus. Because monozygotic twin pairs share the same genotype, our results indicate a strong nongenetic component in arcuate fasciculus asymmetry, particularly in those discordant for cerebral asymmetry.     

Placentation in multiple births.

Outcomes of multifetal pregnancy in prenatal life are markedly affected by chorionicity. Several disease processes are found in monochorionic (MC) twins that do not occur in dichorionic (DC) twins. Improvements in prenatal outcomes will depend on reliable first trimester diagnosis of chorionicity, allowing early monitoring for complications of MC placentation. Particular structures and functions of MC twin placentas affect outcomes and can be targeted for specific treatments, especially in twin-twin transfusion. The causes of severe DC twin fetal growth discordance are clarified. In post-natal life, zygosity is a determining effect in genetic predisposition to many chronic diseases, including neoplasia. Few MC twins know that they are monozygotic (MZ). Few twin researchers realize that MZ twins may be genetically discordant. Abandonment of the word "identical" for MZ twins would assist in clarifying these issues of zygosity, concordance and discordance.     

Methylomic analysis of monozygotic twins discordant for childhood psychotic symptoms

Childhood psychotic symptoms are associated with increased rates of schizophrenia, other psychiatric disorders, and suicide attempts in adulthood; thus, elucidating early risk indicators is crucial to target prevention efforts. There is considerable discordance for psychotic symptoms between monozygotic twins, indicating that child-specific non-genetic factors must be involved. Epigenetic processes may constitute one of these factors and have not yet been investigated in relation to childhood psychotic symptoms. Therefore, this study explored whether differences in DNA methylation at age 10 were associated with monozygotic twin discordance for psychotic symptoms at age 12. The Environmental Risk (E-Risk) Longitudinal Twin Study cohort of 2,232 children (1,116 twin pairs) was assessed for age-12 psychotic symptoms and 24 monozygotic twin pairs discordant for symptoms were identified for methylomic comparison. Children provided buccal samples at ages 5 and 10. DNA was bisulfite modified and DNA methylation was quantified using the Infinium HumanMethylation450 array. Differentially methylated positions (DMPs) associated with psychotic symptoms were subsequently tested in post-mortem prefrontal cortex tissue from adult schizophrenia patients and age-matched controls. Site-specific DNA methylation differences were observed at age 10 between monozygotic twins discordant for age-12 psychotic symptoms. Similar DMPs were not found at age 5. The top-ranked psychosis-associated DMP (cg23933044), located in the promoter of the C5ORF42 gene, was also hypomethylated in post-mortem prefrontal cortex brain tissue from schizophrenia patients compared to unaffected controls. These data tentatively suggest that epigenetic variation in peripheral tissue is associated with childhood psychotic symptoms and may indicate susceptibility to schizophrenia and other mental health problems.     

Birthweight discordance in multiple pregnancy.

This paper reviews several aspects of discordant growth in multiple pregnancies. Discordant growth is not a chance event and therefore several patterns can be discerned. About 75% of twins exhibit < 15% discordance (concordant), 20% are 15-25% (mildly) discordant, and about 5% are more than 25% (severely) discordant. Higher frequencies and increased severity are seen among triplets. Five observations regarding discordance became generally accepted: (a) not all discordant pairs are similar; (b) the larger the discordance level the greater is the risk for an adverse outcome; (c) discordant growth does not necessarily represent growth restriction; (d) a discordance level may have a different clinical implication in different gestational ages; and (e) the smaller fetuses in severely discordant pairs are at disproportionate risk for neonatal mortality. Mild discordance may represent a normal variation between sibs whereas severely discordant pairs often exhibit patterns of growth restriction. Not infrequently, discordance may represent an adaptation to the limited intrauterine space in order to increase gestational age.     

Expression discordance of monozygotic twins at birth: Effect of intrauterine environment and a possible mechanism for fetal programming

Within-pair comparison of monozygotic (MZ) twins provides an ideal model for studying factors that regulate epigenetic profile, by controlling for genetic variation. Previous reports have demonstrated epigenetic variability within MZ pairs, but the contribution of early life exposures to this variation remains unclear. As epigenetic marks govern gene expression, we have used gene expression discordance as a proxy measure of epigenetic discordance in MZ twins at birth in two cell types. We found strong evidence of expression discordance at birth in both cell types and some evidence for higher discordance in twin pairs with separate placentas. Genes previously defined as being involved in response to the external environment showed the most variable expression within pairs, independent of cell type, supporting the idea that even slight differences in intrauterine environment can influence expression profile. Focusing on birthweight, previously identified as a predisposing factor for cardiovascular, metabolic and other complex diseases, and using a statistical model that estimated association based on within-pair variation of expression and birthweight, we found some association between birthweight and expression of genes involved in metabolism and cardiovascular function. This study is the first to examine expression discordance in newborn twins. It provides evidence of a link between birthweight and activity of specific cellular pathways and, as evidence points to gene expression profiles being maintained through cell division by epigenetic factors, provides a plausible biological mechanism for the previously described link between low birthweight and increased risk of later complex disease.     

Increased DNA methylation at the AXIN1 gene in a monozygotic twin from a pair discordant for a caudal duplication anomaly

The AXIN1 gene has been implicated in caudal duplication anomalies. Its coding region was sequenced in both members of a monozygotic (MZ) twin pair discordant for a caudal duplication anomaly, but no mutation was found. Using bisulfite sequencing, we examined methylation at the promoter region of the AXIN1 gene in these twins and in twin and age-matched singleton controls. Methylation of the promoter region in peripheral blood mononucleated cells was variable among individuals, including MZ pairs. In the MZ pair discordant for the caudal duplication, this region of the affected twin was significantly more methylated than that of the unaffected twin (P < .0001), which was significantly more methylated than those of the controls (P = .02). We have confirmed that this CpG island does function as a promoter in vitro and that its activity is inversely proportional to the extent of methylation. This finding raises the possibility that hypermethylation of the AXIN1 promoter, by mechanisms as yet undetermined, is associated with the malformation. This case may be paradigmatic for some cases of MZ discordance.     

Inheritance of quantitative expression of erythrocyte glucose-6-phosphate dehydrogenase activity in the Negro—a twin study

Studies have been conducted on eight sets of monozygous and nine sets of dizygous female Negro twins, both members of whom were heterozygous for G-6-PD deficiency. Twins were studied both by assay of erythrocytic G-6-PD activity and by the methemoglobin elution test (MET). The MET is a procedure which identifies histochemically cells with appreciable G-6-PD activity and permits accurate determination of the percentage of such cells in heterozygotes. Monozygous twins showed significantly less within-pair variation than dizygous twins with both the MET and G-6-PD assay.Concerning the significantly greater agreement in MET results in monozygous twins than dizygous twins, our present working hypothesis is that X-chromosomal inactivation in the Negro female is genetically controlled, rather than random. However, certain alternate hypotheses allowing for random X-inactivation have not been excluded; these include somatic cell selection after random X-inactivation, and cell exchange between identical twins in utero/it. Studies in nontwin related heterozygotes now underway should help differentiate among these various possibilities.In addition to the studies on 17 pairs of female twins heterozygous for G-6-PD deficiency, 26 pairs of nondeficient female Negro twins have been studied by G-6-PD assay. Within-pair variation in monozygous twins was significantly less than within-pair variation in dizygous twins in all cases. The genetic influences detected with the G-6-PD assay in the female twins could theoretically be due to nonrandom X-inactivation, to genetically determined quantitative differences in enzyme activity (e.g., isoalleles), or to both. By appropriate calculations, based on the MET results, we have factored out the effects of X-inactivation on overall enzyme activity in the heterozygous deficient twins. After removal of the effect of X-inactivation, monozygous twins heterozygous for enzyme deficiency continue to show significantly less within-pair variation than dizygous twins. This finding indicates significant genetic influences on quantitative G-6-PD activity other than X-inactivation and other than the deficiency allele. This conclusion has been strengthened by studies on male twins where X-inactivation is not present.Supported by USPHS research grants AM-09381, HE-17544, AM-09919, and HE-03341, by USPHS Career Development Award 1-K3-AM-7959 (Dr. Brewer) and by U.S.A.E.C. Contract (11-1)-1552.     

X inactivation as a source of behavioural differences in monozygotic female twins.

Although members of monozygotic twin pairs are identical in genome sequence, they may differ in patterns of gene expression. One early and irreversible process affecting gene expression, which can create differences within pairs of female monozygotic twins, is X inactivation - one twin can express mainly paternally-received genes on the X chromosome while the other twin expresses mainly maternally-received genes. It follows that non-identical X chromosome expression may cause female monozygotic twins to correlate less strongly than male monozygotic twins on complex behavioural traits affected by X-linked loci. We tested this hypothesis using data from around 4000 same-sex twin pairs on 9 social, behavioural and cognitive measures at ages 2, 3 and 4. Consistent with our hypothesis, monozygotic males were generally more similar than monozygotic females. Three of four significant differences were in traits showing higher correlations in males than females, and these traits - prosocial behaviour, peer problems, and verbal ability - have all been proposed previously in the literature as being influenced by genes on the X chromosome. Interestingly, dizygotic twins showed the reverse pattern of correlations for similar variables, which is also consistent with the X inactivation hypothesis; taken together, then, our monozygotic and dizygotic results suggest the presence of quantitative trait loci on the X chromosome.     

Epigenetic variation during the adult lifespan: cross-sectional and longitudinal data on monozygotic twin pairs

The accumulation of epigenetic changes was proposed to contribute to the age-related increase in the risk of most common diseases. In this study on 230 monozygotic twin pairs (MZ pairs), aged 18-89 years, we investigated the occurrence of epigenetic changes over the adult lifespan. Using mass spectrometry, we investigated variation in global (LINE1) DNA methylation and in DNA methylation at INS, KCNQ1OT1, IGF2, GNASAS, ABCA1, LEP, and CRH, candidate loci for common diseases. Except for KCNQ1OT1, interindividual variation in locus-specific DNA methylation was larger in old individuals than in young individuals, ranging from 1.2-fold larger at ABCA1 (P = 0.010) to 1.6-fold larger at INS (P = 3.7 × 10(-07) ). Similarly, there was more within-MZ-pair discordance in old as compared with young MZ pairs, except for GNASAS, ranging from an 8% increase in discordance each decade at CRH (P = 8.9 × 10(-06) ) to a 16% increase each decade at LEP (P = 2.0 × 10(-08) ). Still, old MZ pairs with strikingly similar DNA methylation were also observed at these loci. After 10-year follow-up in elderly twins, the variation in DNA methylation showed a similar pattern of change as observed cross-sectionally. The age-related increase in methylation variation was generally attributable to unique environmental factors, except for CRH, for which familial factors may play a more important role. In conclusion, sustained epigenetic differences arise from early adulthood to old age and contribute to an increasing discordance of MZ twins during aging.     

Novel Epigenetic Changes Unveiled by Monozygotic Twins Discordant for Smoking Habits

Exposure to cigarette smoking affects the epigenome and could increase the risk of developing diseases such as cancer and cardiovascular disorders. Changes in DNA methylation associated with smoking may help to identify molecular pathways that contribute to disease etiology. Previous studies are not completely concordant in the identification of differentially methylated regions in the DNA of smokers. We performed an epigenome-wide DNA methylation study in a group of monozygotic (MZ) twins discordant for smoking habits to determine the effect of smoking on DNA methylation. As MZ twins are considered genetically identical, this model allowed us to identify smoking-related DNA methylation changes independent from genetic components. We investigated the whole blood genome-wide DNA methylation profiles in 20 MZ twin pairs discordant for smoking habits by using the Illumina HumanMethylation450 BeadChip. We identified 22 CpG sites that were differentially methylated between smoker and non-smoker MZ twins by intra-pair analysis. We confirmed eight loci already described by other groups, located in AHRR, F2RL3, MYOG1 genes, at 2q37.1 and 6p21.33 regions, and also identified several new loci. Moreover, pathway analysis showed an enrichment of genes involved in GTPase regulatory activity. Our study confirmed the evidence of smoking-related DNA methylation changes, emphasizing that well-designed MZ twin models can aid the discovery of novel DNA methylation signals, even in a limited sample population.     

New chromosome 11p15 epigenotypes identified in male monozygotic twins with Beckwith-Wiedemann syndrome

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome demonstrating heterogeneous molecular alterations of two imprinted domains on chromosome 11p15. The most common molecular alterations include loss of methylation at the proximal imprinting center, IC2, paternal uniparental disomy (UPD) of chromosome 11p15 and hypermethylation at the distal imprinting center, IC1. An increased incidence of female monozygotic twins discordant for BWS has been reported. The molecular basis for eleven such female twin pairs has been demonstrated to be a loss of methylation at IC2, whereas only one male monozygotic twin pair has been reported with this molecular defect. We report here two new pairs of male monozygotic twins. One pair is discordant for BWS; the affected twin exhibits paternal UPD for chromosome 11p15 whereas the unaffected twin does not. The second male twin pair is concordant for BWS and both twins of the pair demonstrate hypermethylation at IC1. Thus, this report expands the known molecular etiologies for BWS twins. Interestingly, these findings demonstrate a new epigenotype-phenotype correlation in BWS twins. That is, while female monozygotic twins with BWS are likely to show loss of imprinting at IC2, male monozygotic twins with BWS reflect the molecular heterogeneity seen in BWS singletons. These data underscore the need for molecular testing in BWS twins, especially in view of the known differences among 11p15 epigenotypes with respect to tumor risk.     

Genome-Wide DNA Methylation and Gene Expression Analyses of Monozygotic Twins Discordant for Intelligence Levels

Human intelligence, as measured by intelligence quotient (IQ) tests, demonstrates one of the highest heritabilities among human quantitative traits. Nevertheless, studies to identify quantitative trait loci responsible for intelligence face challenges because of the small effect sizes of individual genes. Phenotypically discordant monozygotic (MZ) twins provide a feasible way to minimize the effects of irrelevant genetic and environmental factors, and should yield more interpretable results by finding epigenetic or gene expression differences between twins. Here we conducted array-based genome-wide DNA methylation and gene expression analyses using 17 pairs of healthy MZ twins discordant intelligently. ARHGAP18, related to Rho GTPase, was identified in pair-wise methylation status analysis and validated via direct bisulfite sequencing and quantitative RT-PCR. To perform expression profile analysis, gene set enrichment analysis (GSEA) between the groups of twins with higher IQ and their co-twins revealed up-regulated expression of several ribosome-related genes and DNA replication-related genes in the group with higher IQ. To focus more on individual pairs, we conducted pair-wise GSEA and leading edge analysis, which indicated up-regulated expression of several ion channel-related genes in twins with lower IQ. Our findings implied that these groups of genes may be related to IQ and should shed light on the mechanism underlying human intelligence.