Discordant Twin Pairs Research Articles

Genetic Epidemiology of Spontaneous Subarachnoid Hemorrhage

It would be essential to clinicians, familial aneurysm study groups, and aneurysm families to understand the genetic basis of subarachnoid hemorrhage (SAH), but there are no large population-based heritability estimates assessing the relative contribution of genetic and environmental factors to SAH. We constructed the largest twin cohort to date, the population-based Nordic Twin Cohort, which comprised 79 644 complete twin pairs of Danish, Finnish, and Swedish origin. The Nordic Twin Cohort was followed up for 6.01 million person-years using nationwide cause-of-death and hospitalization registries. One hundred eighty-eight fatal and 321 nonfatal SAH cases were recorded in the Nordic Twin Cohort. Thus, SAH incidence was 8.47 cases per 100,000 follow-up years. Data for pairwise analyses were available for a total of 504 SAH cases, of which 6 were concordant (5 monozygotic and 1 opposite sex) and 492 discordant twin pairs for SAH. The concordance for SAH in monozygotic twins was 3.1% compared with 0.27% in dizygotic twins, suggesting at most a modest role for genetic factors in the etiology of SAH. The population-based probability estimate for SAH in dizygotic siblings of a patient with SAH is 0.54%, and only 1 of 185 full siblings experience familial SAH. The corresponding risk of SAH in monozygotic twins is 5.9%. Model-fitting, which was based on the comparison of the few monozygotic and dizygotic pairs, suggested that the estimated heritability of SAH is 41%. SAH appears to be mainly of nongenetic origin, and familial SAHs can mostly be attributed to environmental risk factors.

Recurrence risk for offspring of twins discordant for oral cleft: A population‐based cohort study of the Danish 1936–2004 cleft twin cohort

Our objective in this Danish population-based cohort study was to estimate the recurrence risk of isolated oral cleft (OC) for offspring of the unaffected co-twins of OC discordant twin pairs and to compare this risk to the recurrence risk in the offspring of the affected co-twin as well as to the risk in the background population. During 1936-2004, 207 twin pairs were ascertained, among whom at least one twin had an OC. The index persons were twins discordant for OC who had children (N=117), and their offspring (N=239). The participants were ascertained by linkage between The Danish Facial Cleft Database, The Danish Twin Registry and The Danish Civil Registration System. In the study OC recurrence risk for offspring of the affected and unaffected twin and relative risk were compared to the background prevalence. We found that among 110 children of the 54 OC affected twins, two (1.8%) children had OC corresponding to a significantly increased relative risk (RR=10; 95% CI 1.2-35) when compared to the frequency in the background population. Among the 129 children of the 63 unaffected twins, three (2.3%) children were affected, corresponding to a significantly increased relative risk (RR=13; 95% CI 2.6-36) when compared the background prevalence. We concluded that in OC discordant twin pairs similar increased recurrence risks were found among offspring of both OC affected and OC unaffected twins. This provides further evidence for a genetic component in cleft etiology and is useful information for genetic counseling of twin pairs discordant for clefting.

Identical but not the same: The value of discordant monozygotic twins in genetic research

Monozygotic (MZ) twins show remarkable resemblance in many aspects of behavior, health, and disease. Until recently, MZ twins were usually called "genetically identical"; however, evidence for genetic and epigenetic differences within rare MZ twin pairs has accumulated. Here, we summarize the literature on MZ twins discordant for Mendelian inherited disorders and chromosomal abnormalities. A systematic literature search for English articles on discordant MZ twin pairs was performed in Web of Science and PubMed. A total number of 2,016 publications were retrieved and reviewed and 439 reports were retained. Discordant MZ twin pairs are informative in respect to variability of phenotypic expression, pathogenetic mechanisms, epigenetics, and post-zygotic mutagenesis and may serve as a model for research on genetic defects. The analysis of single discordant MZ twin pairs may represent an elegant approach to identify genes in inherited disorders.

Does Educational Status Impact Adult Mortality in Denmark? A Twin Approach

To disentangle an independent effect of educational status on mortality risk from direct and indirect selection mechanisms, the authors used a discordant twin pair design, which allowed them to isolate the effect of education by means of adjustment for genetic and environmental confounding per design. The study is based on data from the Danish Twin Registry and Statistics Denmark. Using Cox regression, they estimated hazard ratios for mortality according to the highest attained education among 5,260 monozygotic and 11,088 dizygotic same-sex twin pairs born during 1921–1950 and followed during 1980–2008. Both standard cohort and intrapair analyses were conducted separately for zygosity, gender, and birth cohort. Educational differences in mortality were demonstrated in the standard cohort analyses but attenuated in the intrapair analyses in all subgroups but men born during 1921–1935, and no effect modification by zygosity was observed. Hence, the results are most compatible with an effect of early family environment in explaining the educational inequality in mortality. However, large educational differences were still reflected in mortality risk differences within twin pairs, thus supporting some degree of independent effect of education. In addition, the effect of education may be more pronounced in older cohorts of Danish men.

Hypospadias in males with intrauterine growth restriction due to placental insufficiency: The placental role in the embryogenesis of male external genitalia

Our aim was to define the association between early onset intra-uterine growth restriction (IUGR) due to placental insufficiency and hypospadias in males. We prospectively studied a cohort of small-for-gestational age (SGA) male infants with hypospadias managed by a multidisciplinary team over a 5-year period. Thirty SGA male infants were diagnosed with hypospadias/abnormal genitalia after birth, and four of them were diagnosed antenatally. Five cases occurred in the smaller pair of discordant IUGR twins, where the larger co-twin had normal male genitalia. Serial ultrasounds demonstrated features of early-onset IUGR in all cases at a median gestational age of 21 weeks (range 14-31weeks). Twenty-one (70%) pregnancies were subsequently complicated by absent/reversed end-diastolic flow in the umbilical arteries indicating severe IUGR, and 17 (57%) women developed severe pre-eclampsia. There were 27 (90%) live births at a median gestational age of 31 weeks (range 27-37); 23 (77%) of the neonates had birth weights <3rd centile. All newborns had normal male karyotypes. In 62% (18/29) the hypospadias was severe. A correlation was found between the severity of the IUGR and the severity of hypospadias as significantly more infants with severe hypospadias were less than the 3rd centile compared to the mild-moderate hypospadias group: 94% (17/18) versus 55% (6/11), respectively (P = 0.02). In conclusion, SGA male newborns with hypospadias exhibit a high rate of early-onset severe IUGR due to placental insufficiency. Early placental development likely influences male external genitalia formation. Careful sonographic evaluation of the genitalia is advised when early-onset placentally mediated IUGR is found.

119: Neonatal outcome in discordant twins - is there a difference between AGA/AGA and AGA/SGA pairs?

To estimate the influence of FGR on neonatal morbidity and mortality among discordant premature twin pairs. Medical records of preterm twins born at 24-37 weeks between 2000 and 2006, were reviewed. Discordancy was defined as a difference of >15% in birth weight. Small for gestational age (SGA) was defined as birth weight <10th percentile, whereas appropriate for gestational age (AGA) was defined as birth weight between the 10th and 90th percentile, according to a twin-adjusted normogram. One group (n=30) included discordant twins which are SGA/AGA pairs and the other group (n=40) included AGA/AGA discordant twin pairs. Neonatal parameters of morbidity and mortality were compared between the pairs of twins. Table 1 depicts the neonatal complications in the AGA/SGA group. The incidence of hyperbilirubinemia, anemia and hypotension were significantly higher among SGA neonates. The incidence of respiratory distress syndrome, apnea and the need for respiratory support was significantly higher among the AGA neonates in the SGA/AGA group. There was no statistically significant difference between the pairs in the incidence of IVH, NEC, sepsis, hyponatremia, hypoglycemia, PDA, neonatal mortality, and length of hospitalization. In the AGA/AGA discordant group there was no difference in any of the neonatal complications between the pairs.Tabled 1AGASGAP valueRDS36.67%16.67%0.014TTN30%3.3%0.004Resp mechan support46.7%16.6%0.003Hyperbilirubin40%70%0.002Phototherapy36.6%66.6%0.003Erythropoietin0%23.3%0.015 Open table in a new tab FGR which leads to SGA among premature twin neonates is associated with significantly lower rates of respiratory morbidity and higher incidence of anemia compared to their AGA sibling. If the discordancy does not lead to SGA, there are no differences between siblings.

Coffee drinking in middle age is not associated with cognitive performance in old age

BackgroundThe lack of effective disease-modifying treatments highlights the need for research on the prevention of dementia. It has been suggested that coffee has a protective effect on cognitive performance in old age, but only some of the previous studies have shown this association. ObjectiveThe aim of our study was to analyze the potential association between coffee drinking in middle age and cognitive performance in old age in a large sample of Finnish twins. DesignCoffee consumption and other baseline variables of 2606 middle-aged Finnish twins were assessed in 1975 and 1981 by postal questionnaires. After the median follow-up of 28 y, their cognitive status was measured by using a validated telephone interview questionnaire. ResultsCoffee consumption was high and associated with educational level and several other baseline variables. After adjustment for these variables, linear regression analysis showed that coffee consumption was not an independent predictor of cognitive performance in old age (β = −0.12 test score units per coffee cup; 95% CI: −0.27, 0.04). No consistent differences in coffee consumption and cognitive score were observed within discordant twin pairs. Also, coffee drinking did not affect the risk of mild cognitive impairment or dementia. ConclusionsCoffee drinking is associated with many sociodemographic and health variables, but our results do not support an independent role of coffee in the pathogenesis of cognitive decline and dementia.

Beyond Heritability

The heritability of human behavioral traits is now well established, due in large measure to classical twin studies. We see little need for further studies of the heritability of individual traits in behavioral science, but the twin study is far from having outlived its usefulness. The existence of pervasive familial influences on behavior means that selection bias is always a concern in any study of the causal effects of environmental circumstances. Twin samples continue to provide new opportunities to identify causal effects with appropriate genetic and shared environmental controls. We discuss environmental studies of discordant twin pairs and twin studies of genetic and environmental transactions in this context.

Physical Activity in Adolescence as a Predictor of Alcohol and Illicit Drug Use in Early Adulthood: A Longitudinal Population-Based Twin Study

We investigated prospectively whether physical activity level in adolescence predicts use of alcohol and illicit drugs in early adulthood. We studied 4,240 individual twins (1,870 twin pairs). We classified those who consistently reported frequent leisure physical activity at ages 16, 17 and 181/2 as persistent exercisers, those exercising less than three times monthly as persistently inactive, and all others as occasional exercisers. To control for familial confounds, within-family analyses compared activity-substance use associations in co-twins discordant for baseline physical activity. Individual-based analyses showed no clear association between baseline physical activity and subsequent weekly alcohol consumption. However, weekly alcohol intoxication (OR = 1.9, p = .002) and problems due to alcohol use (OR = 2.0, p < .001) were more common among persistently inactive participants. After excluding those reporting weekly intoxication at baseline, the risk for alcohol intoxication remained elevated among women occasionally (OR = 2.4, p = .017) or persistently (OR = 5.8, p < .001) inactive at baseline, but this association was not replicated within discordant twin pairs. Individual-based analyses showed that drug use in adulthood was more common among those persistently physically inactive in adolescence (OR = 3.7, p < .001) in comparison to those persistently active. This finding was replicated within discordant twin pairs. Among those with no drug experience during adolescence, persistent inactivity (OR = 1.9, p = .007) increased risk for drug use. We conclude that persistent physical inactivity in adolescence may increase the risk of later problems due to excess alcohol use. Sedentary lifestyle predicts illicit drug use even when controlling for familial factors.

Etiology of Simple Goiter

imple goiter (SG), that is an enlarged nontoxic thyroidgland which is not the result of an inflammatory or neo-plastic process, although on the wane, remains a nearly globalproblem (1,2). Until increasingly employed iodization pro-grams significantly reduces its prevalence, the etiology as wellasthetherapyofbenignnontoxicgoitershouldremaininfocus.It is well accepted that sporadic or endemic SG (2,3), alongwith the other common thyroid diseases co-existing withgoiterincludingGraves’disease(4),toxicmultinodulargoiter,and Hashimoto’s thyroiditis (5), is a complex disease. Theseareallcommonandmultifactorialwiththeclinicalphenotyperepresenting the net effect of many contributing genetic andenvironmental factors. It has been difficult to disentangle en-vironmental influences from genetic susceptibility, progresshasbeenslowinrevealingcandidategenes,andlittleisknownof the roles of gene–environment and gene–gene interaction.AroleforgeneticfactorsintheetiologyofSGhaslongbeenrecognized. Familial aggregation is illustrated by the 5–10times greater prevalence of SG among the probands of firstdegree female relatives as compared with the backgroundpopulation (2,3). Subsequently, twin studies (3), demonstrat-ing a significantly higher concordance rate in monozygotic(53%,95%CI23–83%)thanindizygotictwins(18%,95%CI5–35%), have clarified that the familial aggregation is the resultof shared genes and not of shared environment. Our study ina nonendemic goiter area (3) estimated that heritability oradditivegeneticfactorsaccountedfor82%(95%CI,67–92%)ofcases, while specific individual environmental factors likelyaccounted for 18% (95% CI, 8–33%) of goiter development infemales. The influence of heritability decreases with the pres-ence of major environmental factors such as iodine deficiency(2). As a consequence, susceptibility genes are more easilydiscerned in nonendemic goiter areas. The pronounced influ-ence of heritability on thyroid size (6) and thyroid nodularity(7), with or without concomitant clinical goiter, strengthenstheconceptthatthereisaconsiderablegeneticinfluenceonthedevelopment of SG.A detailed account of the genetic influences on the devel-opment of SG is beyond the scope of this editorial. Mutationsand polymorphisms in the genes for thyroid peroxidase(TPO), thyroglobulin (Tg), sodium iodide symporter (NIS),and thyrotropin receptor (TSHR), however, all have a role (8–10). SG is polygenic, moreover, with no single gene beingeither necessary or sufficient for disease development. Thelimited studies to date suggest that the genetic backgroundvariesfromfamilytofamily.Furthermore,ourunderstandingof the interaction between heredity and environment is verylimited. There is a clear lack of longitudinal studies in indi-viduals with genetically based susceptibility to determinehow and when environmental triggers such as iodine defi-ciency or cigarette smoking influence the occurrence of SG.When studying this issue it is important to realize that SG isnot one single phenotype.The pronounced sex difference in prevalence of thyroiddisease, often 5–10 times more common in females, is puz-zling. Theoretically, a skewed X chromosome inactivation(XCI) pattern—which is probably genetically determined—andresultanttissuechimerismcouldofferanovelexplanationfor the female preponderance of thyroid disorders, includingthat of SG (11). The X chromosome harbors genetic markerslinked to SG (12) and a skewed XCI (i.e., predominant inac-tivation of the normal X chromosome) could result in ex-pression of X-linked diseases. When recently tested, thishypothesis was rejected (13). Intake of oral contraceptives,another potential explanation for the sex-related difference inprevalence of SG, is actually associated with a decreasedthyroid size (14).Whereas environmental influences can be modified whilegenetic background cannot, much of the current focus on theetiology and treatment of SG has been on identifying andcorrectingenvironmentalinfluences.Large-scalestudieshavedemonstrated the importanceof surprisingly small variationsiniodine intake notonly for the prevalence ofovert goiter butalso for the regulation of thyroid size in nongoitrous indi-viduals(15).Interestingly,arelativelysmallincreaseiniodineintake, for just a few years, leads to a measurable and signif-icant decrease in thyroid volume (15), suggesting that modi-fyingiodineintakemayrapidlyleadtoadecreaseinincidenceof SG and subsequently in overt nodular toxic goiter. Studiesof this kind, such as performed in Denmark (16), will un-doubtedly provide further evidence of the interaction be-tween genetic susceptibility and environmental triggers.Another modifiable goitrogen is cigarette smoking. Thereis abundant evidence of its importance, from both case–control studies and studies in discordant twin pairs (17,18).Large-scale studies have demonstrated an interaction be-tween low iodine intake and thiocyanate generating cigarettesmoking, offering an explanation for the effect and providinga means to eliminate one or more factors in the genesis ofgoiter (19).

Long-Term Smoking Behavior Patterns Predicting Self-Reported Chronic Bronchitis

We examined the effects of long-term smoking patterns on self-reported symptoms of chronic bronchitis within the Finnish adult twin cohort including 21, 609 individuals responding to questionnaires in 1975 and 1981, of which 11,015 respondents participated also in 1990. We also explored the association between smoking and bronchitis among discordant twin pairs. Among those without chronic bronchitis at baseline we examined incidence of chronic bronchitis in 1981 both by 1975 smoking status, but also based on subgroups formed according to change in smoking behaviors between 1975 and 1981. We conducted similar analyses in the longitudinal data including three consecutive measurements of smoking status. Logistic regressions demonstrated that among current smokers, the risk of chronic bronchitis increased about 1.5-fold by each amount category of daily cigarettes. When analyzing change of smoking status between 1975 and 1981, daily moderate and heavy smokers, smoking increasers and decreasers, as well as re-current smokers demonstrated elevated risks. In the analysis among discordant twin pairs the smoking co-twins had a 14-fold likelihood for chronic bronchitis compared to their never-smoking co-twins. Panel analyses showed that, not only moderate and heavy, but also former and light smokers, had significant risks for chronic bronchitis. Those with late smoking initiation, leisure time physical activity or over 10 years of smoking cessation were less likely to have chronic bronchitis. We conclude that in long term evaluation no safe level of smoking exists. Abstinence from tobacco seems to be the public health message justified by these results in prevention of chronic bronchitis.

The Role of Birth Weight in Myopia – The Genes in Myopia Twin Study

Objective: It was the aim of this study to assess the role of birth weight in the development of myopia using a large cohort of Caucasian monozygotic (MZ) and dizygotic (DZ) twins that took part in the Genes in Myopia (GEM) twin study. Methods: The recruitment of all twins in the GEM twin study was facilitated by the Australian Twin Registry. Each twin underwent a standard questionnaire and a comprehensive ocular examination, which included a dilated objective refraction through autorefraction. Myopia was defined as spherical equivalent equal to or worse than –0.50 diopters. Birth weight was determined through self-report as part of the standard questionnaire. Results: A total of 1,224 twins (690 MZ and 534 DZ twins) aged between 18 and 86 years (mean age 52.36 years) were recruited into the GEM study. The mean birth weight was similar between MZ (2.34 kg) and DZ twins (2.46 kg; p > 0.05). Logistic regression showed no significant association with birth weight and myopia for all twins (p = 0.26), as well as for MZ (p = 0.18) and DZ twins (p = 0.70) separately, with no gender effect (p = 0.23). Moreover, there was no significant difference in mean birth weight between discordant (presence/absence) MZ (myopes = 2.33 kg, non-myopes = 2.39 kg) and DZ twin pairs (myopes = 2.39 kg, non-myopes = 2.43 kg; p = 0.91 and 0.95, respectively). Conclusion: Birth weight appears to have little to no role in the development of myopia. In addition, birth weight was not a predictor of the discordance of myopia in MZ and DZ twin pairs.

BMI, Weight Stability and Mortality among Adults without Clinical Co-Morbidities: A 22-Year Mortality Follow-Up in the Finnish Twin Cohort

Aim and Method: Cause-specific mortality was studied in relation to body mass index (BMI) and weight stability (defined as less than 1 BMI unit change during a 6-year period) in 15,424 initially healthy twin subjects from the Finnish Twin Cohort, first examined in 1975, re-examined in 1981, and then followed over 22 years (1982–2003). Additionally, death discordant twin pairs were studied to assess whether body weight differences are associated with mortality independent of childhood factors and genetic background. Deaths and cause of death were ascertained from national registries. Associations with mortality were estimated by Cox proportional hazards model for all individuals and conditional logistic regression analysis for pairwise analyses. Results: Mortality increased with increasing BMI for all causes and coronary heart disease (CHD) in men, and there were no associations for all natural causes, cerebrovascular disease, and violent deaths. After adjustment for multiple co-variates and changes in co-variates between 1975 and 1981, BMI was associated with CHD mortality in all men (hazard ratio (HR) = 1.22, 95% CI 1.06–1.41) and in men with stable weight between 1975 and 1981 (HR = 1.26, 95% CI 1.03–1.55). Overall risk of death and cause-specific mortality was not associated with BMI in women. Conclusion: Among clinically healthy subjects at low risk of death, BMI appears to be associated with CHD risk in men.

Differences in Short-Term Neonatal Outcomes Between Discordant Twins

To evaluate short-term outcomes associated with discordant twin pairs admitted to the NICU. A retrospective descriptive study comparing discordant twin pairs. Three hundred eighty-four discordant twin pairs were included. Mean gestational age of the twin pairs was 32.6 weeks (range, 24-39). The ParadigmHealth database was queried for all twin admissions from January 2001 to June 2004 admitted to 453 NICUs across the United States. Discordance was calculated for each twin set as defined as greater than 20% difference in birth weight. Exclusion criteria were death of a twin, congenital anomalies, or extracorporeal life support. Demographics, respiratory needs, feeding characteristics, complications, and discharge needs. A total of 384 discordant twin pairs met inclusion criteria. The larger twins required more ventilation/continuous positive airway pressure (55% vs 44%, P < .01) and/or oxygen therapy (50% vs 41%, P = .02) compared with smaller twins. Smaller twins reached full oral (PO) feeds an average of 0.6 weeks later than larger twins (P < .0001) but had more weight gain per day. Smaller twins transitioned to an open crib at lower weights but at slightly greater age. No differences were noted with necrotizing enterocolitis or apnea. Smaller twins had increased nosocomial infections. Mean length of stay was shorter (P = .0036) in the larger twin group. Only 33% of the twin pairs were discharged on the same day. Larger twins had more acute respiratory issues but achieved certain milestones more rapidly with fewer complications, thus leading to earlier discharge compared with their smaller twin counterparts.

Candidate region linkage analysis in twins discordant or concordant for depression symptomatology

Genetic risk factors contribute considerably to both clinical affective disorders and subsyndromal mood level. There is moreover evidence to suggest that the genetic basis of bipolar disorder and unipolar depression overlap to some extent, and several linkage analyses have suggested evidence for a common susceptibility locus in affective disorders on chromosome 12q24. In this study we investigated the chromosome 12 candidate region for linkage to the mean level of depression symptomatology, over a 10-year follow-up, using a highly informative sample of concordant and discordant twin pairs selected from 4,731 participants of the Longitudinal Study of Ageing Danish Twins. Our results showed suggestive evidence of linkage to this region with a peak LOD score of 1.91 for marker D12S1634 located at 148 cM, and thus indicates that the previously identified disease locus at 12q24 is also a general vulnerability locus affecting the normal range of mood.

Association of the Lipoprotein Lipase Gene T+495G Polymorphism With Central Obesity and Serum Lipids in a Twin Study

The lipoprotein lipase (LPL) gene polymorphism is possibly involved in the pathophysiology of central obesity and dyslipidemia. The aim of this study was to investigate the association of LPL gene T+495G polymorphism with central obesity and serum lipids. A total of 961 adult twin pairs were enrolled from the program of Chinese Twin Registry, between 2001 and 2002. We used 90 cm of waist circumference in male and 80 cm in female as cut-off values of central obesity. The LPL gene T+495G polymorphism was analyzed with the use of genomic polymerase chain reaction and HindIII-restriction fragment length polymorphism. Two statistical methods were performed to test the effect of T+495G polymorphism of LPL gene on the relation between central obesity and lipid levels: one was the generalized estimating equation model for all twin pairs and the other was co-twin matched case-control analysis in 82 central obesity discordant monozygotic twin pairs. In male twins, central obesity was significantly associated with serum lipids except for high-density lipoprotein (HDL). In female twins, obesity twins had significantly higher levels of triglyceride (TG) and TG/HDL than nonobesity twins. There was no significant association between T+495G polymorphism and lipid levels for all twins, although +495G allele carrier was related with 6.7% decrease of TG was observed only in female twins. The interactions of T+495G polymorphism and central obesity were not found for TG, HDL, and TG/HDL. In central obesity discordant monozygotic twin pairs, central obesity was significantly related with 24.2%, 26.1%, and 4.1% increase of TG ,TG/HDL, and TC, respectively, in +495T/T genotype. These results suggest no association and interaction of T+495G polymorphism with central obesity and serum lipids for all twin pairs. Meanwhile, a modest genetic-environmental effect of T+495G polymorphism and central obesity was found in discordant monozygotic twin pairs. Therefore, the +495T/T genotype may be an independent risk factor associated with central obesity and lipids level. However, the role of LPL gene T+195G polymorphism in central obesity and dyslipidemia is complex and remains controversial. This hypothesis needs further investigation.

Epigenetics of Personality Traits: An Illustrative Study of Identical Twins Discordant for Risk-Taking Behavior

DNA methylation differences between identical twins could account for phenotypic twin discordance of behavioral traits and diseases. High throughput epigenomic microarray profiling can be a strategy of choice for identification of epigenetic differences in phenotypically different monozygotic (MZ) twins. Epigenomic profiling of a pair of MZ twins with quantified measures of psychometric discordance identified several DNA methylation differences, some of which may have developmental and behavioral implications and are consistent with the contrasting psychometric profiles of the twins. In particular, differential methylation of CpG islands proximal to the homeobox DLX1 gene could modulate stress responses and risk taking behavior, and deserve further attention as a potential marker of aversion to danger. The epigenetic difference detected at DLX1 of approximately 1.2 fold change was used to evaluate experimental design issues such as the required numbers of technical replicates. It also enabled us to estimate the power this technique would have to detect a functionally relevant epigenetic difference given a range of 1 to 50 twin pairs. We found that use of epigenomic microarray profiling in a relatively small number (15-25) of phenotypically discordant twin pairs has sufficient power to detect 1.2 fold epigenetic changes.

Hypothalamus volume in twin pairs discordant for schizophrenia

Monozygotic and same-sex dizygotic twin pairs discordant for schizophrenia were compared with matched control twin pairs in order to disentangle genetic and environmental contributions to variation in hypothalamus volume. A decrease in hypothalamus volume was found in patients or discordant twin pairs compared to healthy controls which could be attributed to the decrease in total brain volume. Higher within-twin pair similarities in monozygotic compared to dizygotic twin pairs, suggests that hypothalamus volume might be partly genetically controlled.

The neural correlates of verbal encoding and retrieval in monozygotic twins at low or high risk for depression and anxiety

Emotional processing and brain activation were examined during an encoding and recognition paradigm using emotionally salient words in a sample of monozygotic twin pairs at low or high risk for anxiety and depression. Discordant twin pairs were used to chart the effects of environmental risk factors and concordant twin pairs were used to chart the effects of genetic risk factors on performance and brain activation. Performance data did not support the existence of a negative response bias in subjects at high risk. At the neural level, however, increased left inferior frontal gyrus (LIFG) activation by negative words was found in high-risk subjects, most prominently during recognition. Increased LIFG activity was found in subjects at high risk through either genetic or environmental risk factors. These results suggest that fMRI activation of the LIFG in a verbal emotional memory task may be a useful vulnerability marker for anxiety and depression.

Selective Cerebral Volume Reduction in Rett Syndrome: A Multiple-Approach MR Imaging Study

Previous studies have examined volumetric abnormalities in Rett syndrome (RTT), using MR imaging and focusing on selective changes. However, these studies preceded the identification of MECP2 as the gene mutated in most RTT cases. We studied regional brain volume changes as noted by MR imaging in girls with RTT who had mutations in the MECP2 gene and more or less severe clinical outcomes to further characterize the neuroanatomy of RTT and its correlations with clinical severity. Complementary semiautomated Talairach- and voxel-based approaches were used to study spoiled gradient-recalled acquisition sequence MR imaging scans from 23 girls with MECP2 mutations/RTT, including a pair of discordant monozygotic twins and 25 age-matched control girls. Both absolute and relative volumetric changes were examined to account for the well-documented global reduction in brain volume seen in RTT. Absolute volumetric reductions were observed throughout the brain in RTT. Selective/relative decreases in parietal lobe gray matter, particularly in the dorsal parietal region, and mild, diffuse reductions in cortical white matter were observed in the RTT group compared with control subjects. In girls with RTT and a more severe phenotype, anterior frontal lobe volumes were relatively more reduced. Twin comparisons revealed selective preservation of the occipital cortex. Selective reductions of dorsal parietal gray matter and preservation of the occipital cortex seem to be basic neuroanatomic features of RTT, whereas preferential reduction of the anterior frontal lobe appears to be a correlate of clinical severity in this disorder. The most affected brain regions include those that may underlie key functional deficits observed in RTT.