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.

Association of polygenic risk for major psychiatric illness with subcortical volumes and white matter integrity in UK Biobank.

Major depressive disorder (MDD), schizophrenia (SCZ) and bipolar disorder (BP) are common, disabling and heritable psychiatric diseases with a complex overlapping polygenic architecture. Individuals with these disorders, as well as their unaffected relatives, show widespread structural differences in corticostriatal and limbic networks. Structural variation in many of these brain regions is also heritable and polygenic but whether their genetic architecture overlaps with that of major psychiatric disorders is unknown. We sought to address this issue by examining the impact of polygenic risk of MDD, SCZ, and BP on subcortical brain volumes and white matter (WM) microstructure in a large single sample of neuroimaging data; the UK Biobank Imaging study. The first release of UK Biobank imaging data comprised participants with overlapping genetic data and subcortical volumes (N = 978) and WM measures (N = 816). The calculation of polygenic risk scores was based on genome-wide association study results generated by the Psychiatric Genomics Consortium. Our findings indicated no statistically significant associations between either subcortical volumes or WM microstructure, and polygenic risk for MDD, SCZ or BP. These findings suggest that subcortical brain volumes and WM microstructure may not be closely linked to the genetic mechanisms of major psychiatric disorders.

Heritability of tic disorders: a twin-family study.

BACKGROUND: Genetic-epidemiological studies that estimate the contributions of genetic factors to variation in tic symptoms are scarce. We estimated the extent to which genetic and environmental influences contribute to tics, employing various phenotypic definitions ranging between mild and severe symptomatology, in a large population-based adult twin-family sample. METHOD: In an extended twin-family design, we analysed lifetime tic data reported by adult mono- and dizygotic twins (n = 8323) and their family members (n = 7164; parents and siblings) from 7311 families in the Netherlands Twin Register. We measured tics by the abbreviated version of the Schedule for Tourette and Other Behavioral Syndromes. Heritability was estimated by genetic structural equation modeling for four tic disorder definitions: three dichotomous and one trichotomous phenotype, characterized by increasingly strictly defined criteria. RESULTS: Prevalence rates of the different tic disorders in our sample varied between 0.3 and 4.5% depending on tic disorder definition. Tic frequencies decreased with increasing age. Heritability estimates varied between 0.25 and 0.37, depending on phenotypic definitions. None of the phenotypes showed evidence of assortative mating, effects of shared environment or non-additive genetic effects. CONCLUSIONS: Heritabilities of mild and severe tic phenotypes were estimated to be moderate. Overlapping confidence intervals of the heritability estimates suggest overlapping genetic liabilities between the various tic phenotypes. The most lenient phenotype (defined only by tic characteristics, excluding criteria B, C and D of DSM-IV) rendered sufficiently reliable heritability estimates. These findings have implications in phenotypic definitions for future genetic studies.

Self-reported gagging in dentistry: prevalence, psycho-social correlates and oral health.

Although gagging has a profound effect on the delivery of dental care, it is a relatively under-investigated phenomenon. This study aimed to derive a prevalence estimate of gagging during dental treatment based on patient-reported information, to determine some socio-demographic and psychological correlates and to assess the relationship of gagging with self-reported oral health and avoidance of dental care. Data were collected with a survey among Dutch twin families (n = 11 771). Estimated overall prevalence of gagging during dental treatment was 8·2% (95% CI 7·7-8·7). Patients' self-report of gagging was found to be significantly associated with female sex, a lower level of education and higher levels of dental trait anxiety, gagging-related fears (e.g. fear of objects in the mouth), anxious depression and neuroticism. Gagging also appeared to be significantly associated with untreated cavities, gingival bleeding and wearing full dentures, but not with avoidance of dental care. It can be concluded that individuals who report to gag during dental treatment are moderately dentally anxious, fear-specific situations that can trigger a gagging response and, albeit visiting the dentist equally frequently, report to have a poorer oral health compared to those who do not gag.

Is dental phobia a blood-injection-injury phobia?

BACKGROUND: Dental phobia is part of the Blood-Injection-Injury (B-I-I) phobia subtype of specific phobia within DSM-IV-TR. To investigate the conceptual validity of this classification, the purpose of the present study was to determine the co-occurrence of dental phobia, typical dental (and B-I-I related) fears, vasovagal fainting, and avoidance of dental care. METHOD: Data were collected by an online survey in Dutch twin families (n = 11,213). RESULTS: Individuals with a positive screen of dental phobia (0.4% of the sample) rated typical B-I-I-related stimuli as relatively little anxiety provoking (e.g. of all 28 fears the stimulus "the sight of blood" was ranked lowest). Presence of dental phobia was significantly associated with a history of dizziness or fainting during dental treatment (OR = 3.4; 95% CI: 1.5-8.1), but of the dental phobic individuals only 13.0% reported a history of dizziness or fainting during dental treatment. Presence of dental phobia (OR = 5.0; 95% CI: 2.8-8.8) was found to be associated with avoidance of dental care, but a history of dizziness or fainting during dental treatment was not (OR = 1.0; 95% CI: 0.8-1.2). CONCLUSIONS: The present findings converge to the conclusion that dental phobia should be considered a specific phobia subtype independent of the B-I-I cluster within the DSM classification system.

A review and meta-analysis of the heritability of specific phobia subtypes and corresponding fears.

Evidence from twin studies suggests that genetic factors contribute to the risk of developing a fear or a phobia. The aim of the present study was to review the current literature regarding twin studies describing the genetic basis of specific phobias and their corresponding fears. The analysis included five twin studies on fears and ten twin studies on specific phobias. Heritability estimates of fear subtypes and specific phobia subtypes both varied widely, even within the subtypes. A meta-analysis performed on the twin study results indicated that fears and specific phobias are moderately heritable. The highest mean heritability (±SEM) among fear subtypes was found for animal fear (45%±0.004), and among specific phobias for the blood-injury-injection phobia (33%±0.06). For most phenotypes, variance could be explained solely by additive genetic and unique environmental effects. Given the dearth of independent data on the heritability of specific phobias and fears, additional research is needed.

Estimate of the incoherent-scattering contribution to lidar backscatter from clouds.

Lidar backscatter from clouds in the Delft University of Technology experiment is complicated by the fact that the transmitter has a narrow beam width, whereas the receiver has a much wider one. The issue here is whether reception of light scattered incoherently by cloud particles can contribute appreciably to the received power. The incoherent contribution can come from within as well as from outside the transmitter beam but in any case is due to at least two scattering processes in the cloud that are not included in the coherent forward scatter that leads to the usual exponentially attenuated contribution from single-particle backscatter. It is conceivable that a sizable fraction of the total received power within the receiver beam width is due to such incoherent-scattering processes. The ratio of this contribution to the direct (but attenuated) reflection from a single particle is estimated here by means of a distorted-Born approximation to the wave equation (with an incident cw monochromatic wave) and by comparison of the magnitude of the doubly scattered to that of the singly scattered flux. The same expressions are also obtained from a radiative-transfer formalism. The ratio underestimates incoherent multiple scattering when it is not small. Corrections that are due to changes in polarization are noted.