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AbstractIn the course of twin studies whose main focus was elucidation of genetic and environmental factors on behavioral traits, many twin researchers became aware of the strong tendency for dizygotic (DZ) twinning to run in families. Over four decades, Nick Martin and others initiated hormone and ultrasound studies, performed segregation and pedigree analyses, tested candidate genes, carried out linkage projects in sister pairs and formed large collaborations to illuminate the genetics of DZ twinning by genome-wide association studies and meta-analysis. This article summarizes the early work on hormone and genetic studies and describes the meta-analyses that have at last met with success in finding the first genes that predispose to DZ twinning, which also appear to influence many other female reproductive traits.

BACKGROUND: DNA methylation at the GFI1-locus has been repeatedly associated with exposure to smoking from the foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health. METHODS: We meta-analysed the association between DNA methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n = 18,212). DNA methylation at the GFI1-locus was measured in whole-blood. Multivariable regression models were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), diastolic, and systolic blood pressure (BP). FINDINGS: Lower DNA methylation at three out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation at cg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P < 0·012. In contrast, lower DNA methylation at cg09935388, the strongest adult own smoking locus, was associated with decreased BMI, WC, and BP (adjusted 1 × 10-7 < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 × 10-8 < P < 0.001). Lower DNA methylation at all the CpGs was consistently associated with higher TG levels. INTERPRETATION: Epigenetic changes at the GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio-metabolic risk factors. FUND: European Union's Horizon 2020 research and innovation programme under grant agreement no. 633595 DynaHEALTH.

AbstractPaula Bernstein and Elyse Schein are identical twins who were separated at 6 months of age. After spending the first few months of their lives together with a foster mother they were adopted by different families and finally reunited in 2004, when they were 35 years old. The book, Identical Strangers, written by both twins in alternating paragraphs, describes how they found each other after Elyse contacted their adoption agency with a request about information about her biological mother.

AbstractThis paper is the first in a series that aims to give an overview of existing twin registers worldwide. A short description of 16 registries in nine European countries is presented. These registries have access to over 350 000 pairs and a resource for genetic–epidemiological research.

AbstractCohort studies are essential for conducting large studies of multiple exposures and outcomes in humans. Recently, the ability to combine data from multiple cohorts in, for example, meta-analyses, and the willingness in the genetics community to collaborate to enable replication studies has led to many new insights into the genetic and environmental determinants of human health and behaviors. The contribution of Professor Nicholas Martin to the development of cohort studies, particularly of twin and twin-family studies, over a period of several decades is reviewed. He has contributed to the development and use of both Australian and international resources. The contributions of Australian twin studies to genomewide association projects are multiple, and across multiple domains, from biomarkers, lifestyle and behavior to disorders and disease.

Comorbidity — the clustered occurrence of two traits or disorders — may be studied in genetically informative designs such as the classical twin study, to test whether genetic and/or environmental factors underlying the two disorders are correlated. When a genetic correlation is found, this can be explained by several mechanisms, including pleiotropy (the same genes influencing multiple traits), and causality (one trait causing the other). With a cotwin control design, it can be investigated which scenario is most plausible. In this design, monozygotic twin pairs discordant for the first trait (i.e., one twin is affected, the other is not) are compared in terms of their risk for the second trait: under a causal model, only the twins affected for the first trait will be at increased risk for the second trait. Under genetic pleiotropy, this risk will be increased in both twins because they share the same risk genes. We first discuss the cotwin control design and then illustrate its application with data on migraine and neuroticism that were collected in 5,200 Dutch twins, including 1,648 complete twin pairs (981 monozygotic and 667 dizygotic pairs). There was a significant association between migraine and neuroticism, which could be attributed to genetic and environmental correlations (rG = .27 and rE = .19). In monozygotic and dizygotic twin pairs discordant for neuroticism, the risk of migraine was significantly higher in the twins with a high neuroticism score. This pattern of results is consistent with a causal relationship, suggesting that neuroticism increases the risk of migraine.

AbstractEvidence for a relation between neuroticism and religion is scarce and inconsistent. The aims of the present study were to determine the association of religious upbringing with adult neuroticism scores and to examine the effect of religious upbringing on the heritability of neuroticism. As part of a longitudinal survey of twin families from the Netherlands Twin Register, data were collected on neuroticism and religious upbringing. Restricting the sample to persons aged 25 and over resulted in a sample of 4369 twins and 1304 siblings from 2698 families. Religious upbringing was significantly associated with neuroticism; in both men and women neuroticism levels were lower in those who had received a religious upbringing. There were no sex or twinsibling differences in neuroticism variances and covariances. Structural equation modeling showed differences in heritability between those with and without religious upbringing. In the group with religious upbringing, variation in neuroticism was determined for 41% by additive genetic factors and for the remaining 59% by unique environmental factors. In the group who had not received a religious upbringing, variation in neuroticism was determined for 55% by genetic factors, with evidence for both additive and nonadditive factors, and for the remaining 45% by unique environmental influences. In conclusion, having received a religious upbringing is associated with lower neuroticism scores and a lower heritability in adulthood.

AbstractA transmission disequilibrium test for quantitative traits which combines association and linkage analyses is currently available in several dedicated software packages. We describe how to implement such models in linear mixed model procedures that are available in widely used statistical packages such as SPSS. We also briefly mention a few extensions of the model that become naturally available once the model is implemented in such procedures.