Male microchimerism in females: a quantitative study of twin pedigrees to investigate mechanisms.

STUDY QUESTION: Does having a male co-twin, older brothers, or sons lead to an increased probability of persistent male microchimerism in female members of twin pedigrees? SUMMARY ANSWER: The presence of a male co-twin did not increase risk of male microchimerism and the prevalence of male microchimerism was not explained by having male offspring or by having an older brother. WHAT IS KNOWN ALREADY: Microchimerism describes the presence of cells within an organism that originate from another zygote and is commonly described as resulting from pregnancy in placental mammals. It is associated with diseases with a female predilection including autoimmune diseases and pregnancy-related complications. However, microchimerism also occurs in nulliparous women; signifying gaps in the understanding of risk factors contributing to persistent microchimerism and the origin of the minor cell population. STUDY DESIGN, SIZE, DURATION: This cross-sectional study composed of 446 adult female participants of the Netherlands Twin Register (NTR). PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants included in the study were female monozygotic (MZ) twins, female dizygotic same-sex twins and females of dizygotic opposite-sex twin pairs, along with the mothers and sisters of these twins. Peripheral blood samples collected from adult female participants underwent DNA extraction and were biobanked prior to the study. To detect the presence of male-origin microchimerism, DNA samples were tested for the relative quantity of male specific Y chromosome gene DYS14 compared to a common ß-globin gene using a highly sensitive quantitative PCR assay. MAIN RESULTS AND THE ROLE OF CHANCE: We observed a large number of women (26.9%) having detectable male microchimerism in their peripheral blood samples. The presence of a male co-twin did not increase risk of male microchimerism (odds ratio (OR) = 1.23: SE 0.40, P = 0.61) and the prevalence of male microchimerism was not explained by having male offspring (OR 0.90: SE 0.19, P = 0.63) or by having an older brother (OR = 1.46: SE 0.32, P = 0.09). The resemblance (correlation) for the presence of microchimerism was similar (P = 0.66) in MZ pairs (0.27; SE 0.37) and in first-degree relatives (0.091; SE 0.092). However, age had a positive relationship with the presence of male microchimerism (P = 0.02). LIMITATIONS, REASONS FOR CAUTION: After stratifying for variables of interest, some participant groups resulted in a low numbers of subjects. We investigated microchimerism in peripheral blood due to the proposed mechanism of cell acquisition via transplacental blood exchange; however, this does not represent global chimerism in the individual and microchimerism may localize to numerous other tissues. WIDER IMPLICATIONS OF THE FINDINGS: Immune regulation during pregnancy is known to mitigate allosensitization and support tolerance to non-inherited antigens found on donor cells. While unable to identify a specific source that promotes microchimerism prevalence within pedigrees, this study points to the underlying complexities of natural microchimerism in the general population. These findings support previous studies which have identified the presence of male microchimerism among women with no history of pregnancy, suggesting alternative sources of microchimerism. The association of detectable male microchimerism with age is suggestive of additional factors including time, molecular characteristics and environment playing a critical role in the prevalence of persistent microchimerism. The present study necessitates investigation into the molecular underpinnings of natural chimerism to provide insight into women's health, transplant medicine and immunology. STUDY FUNDING/COMPETING INTEREST(S): This work is funded by Royal Netherlands Academy of Science Professor Award (PAH/6635 to D.I.B.); The Netherlands Organisation for Health Research and Development (ZonMw)-Genotype/phenotype database for behavior genetic and genetic epidemiological studies (ZonMw 911-09-032); Biobanking and Biomolecular Research Infrastructure (BBMRI-NL, 184.021.007; 184.033.111); The Netherlands Organisation for Scientific Research (NWO)-Netherlands Twin Registry Repository (NWO-Groot 480-15-001/674); the National Institutes of Health-The Rutgers University Cell and DNA Repository cooperative agreement (NIMH U24 MH068457-06), Grand Opportunity grants Integration of genomics and transcriptomics in normal twins and major depression (NIMH 1RC2 MH089951-01), and Developmental trajectories of psychopathology (NIMH 1RC2 MH089995); and European Research Council-Genetics of Mental Illness (ERC 230374). C.B.L. declares a competing interest as editor-in-chief of Human Reproduction and his department receives unrestricted research grants from Ferring, Merck and Guerbet. All remaining authors have no conflict-of-interest to declare in regards to this work. TRIAL REGISTRATION NUMBER: N/A.

Ketone body 3-hydroxybutyrate as a biomarker of aggression.

Human aggression is a complex behaviour, the biological underpinnings of which remain poorly known. To gain insights into aggression biology, we studied relationships with aggression of 11 low-molecular-weight metabolites (amino acids, ketone bodies), processed using 1H nuclear magnetic resonance spectroscopy. We used a discovery sample of young adults and an independent adult replication sample. We studied 725 young adults from a population-based Finnish twin cohort born 1983-1987, with aggression levels rated in adolescence (ages 12, 14, 17) by multiple raters and blood plasma samples at age 22. Linear regression models specified metabolites as the response variable and aggression ratings as predictor variables, and included several potential confounders. All metabolites showed low correlations with aggression, with only one-3-hydroxybutyrate, a ketone body produced during fasting-showing significant (negative) associations with aggression. Effect sizes for different raters were generally similar in magnitude, while teacher-rated (age 12) and self-rated (age 14) aggression were both significant predictors of 3-hydroxybutyrate in multi-rater models. In an independent replication sample of 960 adults from the Netherlands Twin Register, higher aggression (self-rated) was also related to lower levels of 3-hydroxybutyrate. These exploratory epidemiologic results warrant further studies on the role of ketone metabolism in aggression.

Multilevel Twin Models: Geographical Region as a Third Level Variable.

The classical twin model can be reparametrized as an equivalent multilevel model. The multilevel parameterization has underexplored advantages, such as the possibility to include higher-level clustering variables in which lower levels are nested. When this higher-level clustering is not modeled, its variance is captured by the common environmental variance component. In this paper we illustrate the application of a 3-level multilevel model to twin data by analyzing the regional clustering of 7-year-old children's height in the Netherlands. Our findings show that 1.8%, of the phenotypic variance in children's height is attributable to regional clustering, which is 7% of the variance explained by between-family or common environmental components. Since regional clustering may represent ancestry, we also investigate the effect of region after correcting for genetic principal components, in a subsample of participants with genome-wide SNP data. After correction, region no longer explained variation in height. Our results suggest that the phenotypic variance explained by region might represent ancestry effects on height.

[Psychopathology, risk factors and possible interventions in the early years: Dutch cohort research]. / Risicofactoren voor psychische problemen en mogelijke interventies in de jonge jaren: Nederlands cohortonderzoek.

Background Multiple factors contribute to the development of psychiatric disorders. Aim To discuss factors in pregnancy and early childhood that contribute to the development of psychiatric problems. Method Overview of the findings of four major Dutch child cohorts. Results Based on findings of four major Dutch child cohorts, we describe risk factors during pregnancy and early childhood that contribute to the development of psychopathology. Conclusion The identified risk factors and mechanisms can serve as targets for follow-up research, prevention, and intervention. Tijdschrift voor psychiatrie 63(2021)2, 107-110.

Parental Age in Relation to Offspring's Neurodevelopment.

Objective: Advanced parenthood increases the risk of severe neurodevelopmental disorders like autism, Down syndrome and schizophrenia. Does advanced parenthood also negatively impact offspring's general neurodevelopment?Method: We analyzed child-, father-, mother- and teacher-rated attention-problems (N = 38,024), and standardized measures of intelligence (N = 10,273) and educational achievement (N = 17,522) of children from four Dutch population-based cohorts. The mean age over cohorts varied from 9.73-13.03. Most participants were of Dutch origin, ranging from 58.7%-96.7% over cohorts. We analyzed 50% of the data to generate hypotheses and the other 50% to evaluate support for these hypotheses. We aggregated the results over cohorts with Bayesian research synthesis.Results: We mostly found negative linear relations between parental age and attention-problems, meaning that offspring of younger parents tended to have more attention problems. Maternal age was positively and linearly related to offspring's IQ and educational achievement. Paternal age showed an attenuating positive relation with educational achievement and an inverted U-shape relation with IQ, with offspring of younger and older fathers at a disadvantage. Only the associations with maternal age remained after including SES. The inclusion of child gender in the model did not affect the relation between parental age and the study outcomes.Conclusions: Effects were small but significant, with better outcomes for children born to older parents. Older parents tended to be of higher SES. Indeed, the positive relation between parental age and offspring neurodevelopmental outcomes was partly confounded by SES.

Testing sampling bias in estimates of adolescent social competence and behavioral control.

In 5 of the 6 large Dutch developmental cohorts investigated here, lower SES adolescents are underrepresented and higher SES adolescents overrepresented. With former studies clearly revealing differences between SES strata in adolescent social competence and behavioral control, this misrepresentation may contribute to an overestimation of normative adolescent competence. Using a raking procedure, we used national census statistics to weigh the cohorts to be more representative of the Dutch population. Contrary to our expectations, in all cohorts, little to no differences between SES strata were found in the two outcomes. Accordingly, no differences between weighted and unweighted mean scores were observed across all cohorts. Furthermore, no clear change in correlations between social competence and behavioral control was found. These findings are most probably explained by the fact that measures of SES in the samples were quite limited, and the low SES participants in the cohorts could not be considered as representative of the low SES groups in the general population. Developmental outcomes associated with SES may be affected by a raking procedure in other cohorts that have a sufficient number and sufficient variation of low SES adolescents.

Robust longitudinal multi-cohort results: The development of self-control during adolescence.

Longitudinal data from multiple cohorts may be analyzed by Bayesian research synthesis. Here, we illustrate this approach by investigating the development of self-control between age 13 and 19 and the role of sex therein in a multi-cohort, longitudinal design. Three Dutch cohorts supplied data: the Netherlands Twin Register (NTR; N = 21,079), Research on Adolescent Development and Relationships-Young (RADAR-Y; N = 497), and Tracking Adolescents' Individual Lives Survey (TRAILS; N = 2229). Self-control was assessed by one measure in NTR and RADAR-Y, and three measures in TRAILS. In each cohort, we evaluated evidence for competing informative hypotheses regarding the development of self-control. Subsequently, we aggregated this evidence over cohorts and measures to arrive at a robust conclusion that was supported by all cohorts and measures. We found robust evidence for the hypothesis that on average self-control increases during adolescence (i.e., maturation) and that individuals with lower initial self-control often experience a steeper increase in self-control (i.e., a pattern of recovery). From self-report, boys have higher initial self-control levels at age 13 than girls, whereas parents report higher self-control for girls.

An Extended Twin-Pedigree Study of Different Classes of Voluntary Exercise Behavior.

We investigated the familial clustering of different classes of voluntary regular exercise behavior in extended twin-family pedigrees. In contrast to the earlier work based on twin data only, this allowed us to estimate the contributions of shared household effects (C), additive (A), and non-additive (D) genetic effects on voluntary exercise behavior. To test whether shared household effects were inflated by assortative mating we examined the causes of spousal resemblance. For adolescent and adult participants (aged 16 to 65) in the Netherlands Twin Register we constructed 19,543 pedigrees which specified all relations among nuclear family members and larger families in the register (N = 50,690 individuals). Data were available on total weekly MET minutes spent on leisure time exercise, and on total weekly MET minutes spent on exercise activities in team-based, solitary, competitive, non-competitive, externally paced and internally paced exercise. We analyzed the data in the Mendel software package (Lange et al. in Bioinformatics 29(12):1568-1570, 2013) under multiple definitions of household sharing and used data from spouses of twins to test phenotypic assortment, social homogamy, and marital interaction as potential sources of spousal resemblance. Results confirmed the influence of genetic factors on the total volume of weekly exercise behavior throughout the life span. Broad sense heritability ranged from 34 to 41% (19-26% A, 12-21% D), and did not depend on the definition for household sharing. Engaging in team-based, competitive, externally paced activities (e.g., soccer) was ~ 13% more heritable than engaging in non-competitive, solitary activities (e.g., jogging). Having shared a household as siblings explained 4-8% of the variance in adult exercise behavior, whereas sharing a household by spouses yielded higher C estimates (20-24%), as it incorporates spousal resemblance. Spousal resemblance was explained by both social homogamy and marital interaction, with little evidence for phenotypic assortment. We conclude that both the amount of voluntary exercise behavior and the preference for specific classes of exercise activities in adults is explained by additive and non-additive genetic factors and unique environmental influences that include correlated exercise behavior of spouses.

Comparing the genetic architecture of childhood behavioral problems across socioeconomic strata in the Netherlands and the United Kingdom.

Socioeconomic status (SES) affects the development of childhood behavioral problems. It has been frequently observed that children from low SES background tend to show more behavioral problems. There also is some evidence that SES has a moderating effect on the causes of individual differences in childhood behavioral problems, with lower heritability estimates and a stronger contribution of environmental factors in low SES groups. The aim of the present study was to examine whether the genetic architecture of childhood behavioral problems suggests the presence of protective and/or harmful effects across socioeconomic strata, in two countries with different levels of socioeconomic disparity: the Netherlands and the United Kingdom. We analyzed data from 7-year-old twins from the Netherlands Twin Register (N = 24,112 twins) and the Twins Early Development Study (N = 19,644 twins). The results revealed a nonlinear moderation effect of SES on the contribution of genetic and environmental factors to individual differences in childhood behavioral problems. The heritability was higher, the contribution of the shared environment was lower, and the contribution of the nonshared environment was higher, for children from high SES families, compared to children from low or medium SES families. The pattern was similar for Dutch and UK families. We discuss the importance of these findings for prevention and intervention goals.

Low prevalence of male microchimerism in women with Mayer-Rokitansky-Küster-Hauser syndrome.

STUDY QUESTION: Is there an increased prevalence of male microchimerism in women with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, as evidence of fetal exposure to blood and anti-Müllerian hormone (AMH) from a (vanished) male co-twin resulting in regression of the Müllerian duct derivatives? SUMMARY ANSWER: Predominant absence of male microchimerism in adult women with MRKH syndrome does not support our hypothesis that intrauterine blood exchange with a (vanished) male co-twin is the pathophysiological mechanism. WHAT IS KNOWN ALREADY: The etiology of MRKH is unclear. Research on the phenotype analogous condition in cattle (freemartinism) has yielded the hypothesis that Müllerian duct development is inhibited by exposure to AMH in utero. In cattle, the male co-twin has been identified as the source for AMH, which is transferred via placental blood exchange. In human twins, a similar exchange of cellular material has been documented by detection of chimerism, but it is unknown whether this has clinical consequences. STUDY DESIGN, SIZE, DURATION: An observational case-control study was performed to compare the presence of male microchimerism in women with MRKH syndrome and control women. Through recruitment via the Dutch patients' association of women with MRKH (comprising 300 members who were informed by email or regular mail), we enrolled 96 patients between January 2017 and July 2017. The control group consisted of 100 women who reported never having been pregnant. PARTICIPANTS/MATERIALS, SETTING, METHODS: After written informed consent, peripheral blood samples were obtained by venipuncture, and genomic DNA was extracted. Male microchimerism was detected by Y-chromosome-specific real-time quantitative PCR, with use of DYS14 marker. Possible other sources for microchimerism, for example older brothers, were evaluated using questionnaire data. MAIN RESULTS AND THE ROLE OF CHANCE: The final analysis included 194 women: 95 women with MRKH syndrome with a mean age of 40.9 years and 99 control women with a mean age of 30.2 years. In total, 54 women (56.8%) were identified as having typical MRKH syndrome, and 41 women (43.2%) were identified as having atypical MRKH syndrome (when extra-genital malformations were present). The prevalence of male microchimerism was significantly higher in the control group than in the MRKH group (17.2% versus 5.3%, P = 0.009). After correcting for age, women in the control group were 5.8 times more likely to have male microchimerism (odds ratio 5.84 (CI 1.59-21.47), P = 0.008). The mean concentration of male microchimerism in the positive samples was 56.0 male genome equivalent per 1 000 000 cells. The prevalence of male microchimerism was similar in women with typical MRKH syndrome and atypical MRKH syndrome (5.6% versus 4.9%, P = 0.884). There were no differences between women with or without microchimerism in occurrence of alternative sources of XY cells, such as older brothers, previous blood transfusion, or history of sexual intercourse. LIMITATIONS, REASON FOR CAUTION: We are not able to draw definitive conclusions regarding the occurrence of AMH exchange during embryologic development in women with MRKH syndrome. Our subject population includes all adult women and therefore is reliant on long-term prevalence of microchimerism. Moreover, we have only tested blood, and, theoretically, the cells may have grafted anywhere in the body during development. It must also be considered that the exchange of AMH may occur without the transfusion of XY cells and therefore cannot be discovered by chimerism detection. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to test the theory that freemartinism causes the MRKH syndrome in humans. The study aimed to test the presence of male microchimerism in women with MRKH syndrome as a reflection of early fetal exposure to blood and AMH from a male (vanished) co-twin. We found that male microchimerism was only present in 5.3% of the women with MRKH syndrome, a significantly lower percentage than in the control group (17.2%). Our results do not provide evidence for an increased male microchimerism in adult women with MRKH as a product of intrauterine blood exchange. However, the significant difference in favor of the control group is of interest to the ongoing discussion on microchimeric cell transfer and the possible sources of XY cells. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: Dutch trial register, NTR5961.

Correction to: A Genetic Investigation of the Well-Being Spectrum.

In the original version of this article, unfortunately, in the acknowledgement section "National Institutes of Health (NIH, R37 AG033590-08) to J Cacioppo" was omitted. This has been corrected by publishing this erratum.

A Genetic Investigation of the Well-Being Spectrum.

The interrelations among well-being, neuroticism, and depression can be captured in a so-called well-being spectrum (3-phenotype well-being spectrum, 3-WBS). Several other human traits are likely linked to the 3-WBS. In the present study, we investigate how the 3-WBS can be expanded. First, we constructed polygenic risk scores for the 3-WBS and used this score to predict a series of traits that have been associated with well-being in the literature. We included information on loneliness, big five personality traits, self-rated health, and flourishing. The 3-WBS polygenic score predicted all the original 3-WBS traits and additionally loneliness, self-rated health, and extraversion (R2 between 0.62% and 1.58%). Next, using LD score regression, we calculated genetic correlations between the 3-WBS and the traits of interest. From all candidate traits, loneliness and self-rated health were found to have the strongest genetic correlations (rg = - 0.79, and rg= 0.64, respectively) with the 3-WBS. Lastly, we use Genomic SEM to investigate the factor structure of the proposed spectrum. The best model fit was obtained for a two-factor model including the 5-WBS traits, with two highly correlated factors representing the negative- and positive end of the spectrum. Based on these analyses we propose to include loneliness and self-rated health in the WBS and use a 5-phenotype well-being spectrum in future studies to gain more insight into the determinants of human well-being.

A Potential Role for the STXBP5-AS1 Gene in Adult ADHD Symptoms.

We aimed to detect Attention-deficit/hyperactivity (ADHD) risk-conferring genes in adults. In children, ADHD is characterized by age-inappropriate levels of inattention and/or hyperactivity-impulsivity and may persists into adulthood. Childhood and adulthood ADHD are heritable, and are thought to represent the clinical extreme of a continuous distribution of ADHD symptoms in the general population. We aimed to leverage the power of studies of quantitative ADHD symptoms in adults who were genotyped. Within the SAGA (Study of ADHD trait genetics in adults) consortium, we estimated the single nucleotide polymorphism (SNP)-based heritability of quantitative self-reported ADHD symptoms and carried out a genome-wide association meta-analysis in nine adult population-based and case-only cohorts of adults. A total of n = 14,689 individuals were included. In two of the SAGA cohorts we found a significant SNP-based heritability for self-rated ADHD symptom scores of respectively 15% (n = 3656) and 30% (n = 1841). The top hit of the genome-wide meta-analysis (SNP rs12661753; p-value = 3.02 × 10-7) was present in the long non-coding RNA gene STXBP5-AS1. This association was also observed in a meta-analysis of childhood ADHD symptom scores in eight population-based pediatric cohorts from the Early Genetics and Lifecourse Epidemiology (EAGLE) ADHD consortium (n = 14,776). Genome-wide meta-analysis of the SAGA and EAGLE data (n = 29,465) increased the strength of the association with the SNP rs12661753. In human HEK293 cells, expression of STXBP5-AS1 enhanced the expression of a reporter construct of STXBP5, a gene known to be involved in "SNAP" (Soluble NSF attachment protein) Receptor" (SNARE) complex formation. In mouse strains featuring different levels of impulsivity, transcript levels in the prefrontal cortex of the mouse ortholog Gm28905 strongly correlated negatively with motor impulsivity as measured in the five choice serial reaction time task (r2 = - 0.61; p = 0.004). Our results are consistent with an effect of the STXBP5-AS1 gene on ADHD symptom scores distribution and point to a possible biological mechanism, other than antisense RNA inhibition, involved in ADHD-related impulsivity levels.

Predicting loneliness with polygenic scores of social, psychological and psychiatric traits.

Loneliness is a heritable trait that accompanies multiple disorders. The association between loneliness and mental health indices may partly be due to inherited biological factors. We constructed polygenic scores for 27 traits related to behavior, cognition and mental health and tested their prediction for self-reported loneliness in a population-based sample of 8798 Dutch individuals. Polygenic scores for major depressive disorder (MDD), schizophrenia and bipolar disorder were significantly associated with loneliness. Of the Big Five personality dimensions, polygenic scores for neuroticism and conscientiousness also significantly predicted loneliness, as did the polygenic scores for subjective well-being, tiredness and self-rated health. When including all polygenic scores simultaneously into one model, only 2 major depression polygenic scores remained as significant predictors of loneliness. When controlling only for these 2 MDD polygenic scores, only neuroticism and schizophrenia remain significant. The total variation explained by all polygenic scores collectively was 1.7%. The association between the propensity to feel lonely and the susceptibility to psychiatric disorders thus pointed to a shared genetic etiology. The predictive power of polygenic scores will increase as the power of the genome-wide association studies on which they are based increases and may lead to clinically useful polygenic scores that can inform on the genetic predisposition to loneliness and mental health.

Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence.

Cigarette smoking is a leading cause of preventable mortality worldwide. Nicotine dependence, which reduces the likelihood of quitting smoking, is a heritable trait with firmly established associations with sequence variants in nicotine acetylcholine receptor genes and at other loci. To search for additional loci, we conducted a genome-wide association study (GWAS) meta-analysis of nicotine dependence, totaling 38,602 smokers (28,677 Europeans/European Americans and 9925 African Americans) across 15 studies. In this largest-ever GWAS meta-analysis for nicotine dependence and the largest-ever cross-ancestry GWAS meta-analysis for any smoking phenotype, we reconfirmed the well-known CHRNA5-CHRNA3-CHRNB4 genes and further yielded a novel association in the DNA methyltransferase gene DNMT3B. The intronic DNMT3B rs910083-C allele (frequency=44-77%) was associated with increased risk of nicotine dependence at P=3.7 × 10-8 (odds ratio (OR)=1.06 and 95% confidence interval (CI)=1.04-1.07 for severe vs mild dependence). The association was independently confirmed in the UK Biobank (N=48,931) using heavy vs never smoking as a proxy phenotype (P=3.6 × 10-4, OR=1.05, and 95% CI=1.02-1.08). Rs910083-C is also associated with increased risk of squamous cell lung carcinoma in the International Lung Cancer Consortium (N=60,586, meta-analysis P=0.0095, OR=1.05, and 95% CI=1.01-1.09). Moreover, rs910083-C was implicated as a cis-methylation quantitative trait locus (QTL) variant associated with higher DNMT3B methylation in fetal brain (N=166, P=2.3 × 10-26) and a cis-expression QTL variant associated with higher DNMT3B expression in adult cerebellum from the Genotype-Tissue Expression project (N=103, P=3.0 × 10-6) and the independent Brain eQTL Almanac (N=134, P=0.028). This novel DNMT3B cis-acting QTL variant highlights the importance of genetically influenced regulation in brain on the risks of nicotine dependence, heavy smoking and consequent lung cancer.

Genome-wide meta-analysis of cognitive empathy: heritability, and correlates with sex, neuropsychiatric conditions and cognition.

We conducted a genome-wide meta-analysis of cognitive empathy using the 'Reading the Mind in the Eyes' Test (Eyes Test) in 88,056 research volunteers of European Ancestry (44,574 females and 43,482 males) from 23andMe Inc., and an additional 1497 research volunteers of European Ancestry (891 females and 606 males) from the Brisbane Longitudinal Twin Study. We confirmed a female advantage on the Eyes Test (Cohen's d=0.21, P<2.2 × 10-16), and identified a locus in 3p26.1 that is associated with scores on the Eyes Test in females (rs7641347, Pmeta=1.58 × 10-8). Common single nucleotide polymorphisms explained 5.8% (95% CI: 4.5%-7.2%; P=1.00 × 10-17) of the total trait variance in both sexes, and we identified a twin heritability of 28% (95% CI: 13%-42%). Finally, we identified significant genetic correlation between the Eyes Test and anorexia nervosa, openness (NEO-Five Factor Inventory), and different measures of educational attainment and cognitive aptitude.

Functional and effective whole brain connectivity using magnetoencephalography to identify monozygotic twin pairs.

Resting-state functional connectivity patterns are highly stable over time within subjects. This suggests that such 'functional fingerprints' may have strong genetic component. We investigated whether the functional (FC) or effective (EC) connectivity patterns of one monozygotic twin could be used to identify the co-twin among a larger sample and determined the overlap in functional fingerprints within monozygotic (MZ) twin pairs using resting state magnetoencephalography (MEG). We included 32 cognitively normal MZ twin pairs from the Netherlands Twin Register who participate in the EMIF-AD preclinAD study (average age 68 years). Combining EC information across multiple frequency bands we obtained an identification rate over 75%. Since MZ twin pairs are genetically identical these results suggest a high genetic contribution to MEG-based EC patterns, leading to large similarities in brain connectivity patterns between two individuals even after 60 years of life or more.

Genome-wide association study of borderline personality disorder reveals genetic overlap with bipolar disorder, major depression and schizophrenia.

Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case-control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10-7) and PKP4 (P=8.67 × 10-7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10-3]), SCZ (rg=0.34 [P=4.37 × 10-5]) and MDD (rg=0.57 [P=1.04 × 10-3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.