Utilizing a newly released cognitive Polygenic Score (PGS) from Wave IV of Add Health (n = 1,886), structural equation models (SEMs) examining the relationship between PGS and fertility (which is approximately 50% complete in the present sample), employing measures of verbal IQ and educational attainment as potential mediators, were estimated. The results of indirect pathway models revealed that verbal IQ mediates the positive relationship between PGS and educational attainment, and educational attainment in turn mediates the negative relationship between verbal IQ and a latent fertility measure. The direct path from PGS to fertility was non-significant. The model was robust to controlling for age, sex, and race; furthermore, the results of a multigroup SEM revealed no significant differences in the estimated path coeficients across sex. These results indicate that those predisposed towards higher verbal IQ by virtue of higher PGS values are also predisposed towards trading fertility against time spent in education, which contributes to those with higher PGS values producing fewer offspring at this stage in their life course.

Migraine is classified by the World Health Organization (WHO) as being one of the top 20 most debilitating diseases. According to the neurovascular hypothesis, neuroinflammation may promote the activation and sensitisation of meningeal nociceptors, inducing the persistent throbbing headache characterized in migraine. The tumor necrosis factor (TNF) gene cluster, made up of TNFα, lymphotoxin α (LTA), and lymphotoxin β (LTB), has been implicated to influence the intensity and duration of local inflammation. It is thought that sterile inflammation mediated by LTA, LTB, and TNFα contributes to threshold brain excitability, propagation of neuronal hyperexcitability and thus initiation and maintenance of a migraine attack. Previous studies have investigated variants within the TNF gene cluster region in relation to migraine susceptibility, with largely conflicting results. The aim of this study was to expand on previous research and utilize a large case-control cohort and range of variants within the TNF gene cluster to investigate the role of the TNF gene cluster in migraine. Nine single nucleotide polymorphisms (SNPs) were selected for investigation as follows: rs1800683, rs2229094, rs2009658, rs2071590, rs2239704, rs909253, rs1800630, rs1800629, and rs3093664. No significant association with migraine susceptibility was found for any of the SNPs tested, with further testing according to migraine subtype and gender also showing no association for disease risk. Haplotype analysis showed that none of the tested haplotypes were significantly associated with migraine.

The Minnesota Twin Family Study is a longitudinal study of 11-year-old and 17-year-old twins and their parents designed to examine factors related to the etiology of substance abuse and related problems. At study intake, the twins and their parents participate in a day-long assessment in our laboratory that includes measures of endophenotypes (e.g., event-related potentials, EEG, autonomic nervous system reactivity, startle eye-blink), psychopathology, personality, cognitive ability, anthropometry, and environmental risk/protective factors. DNA derived from blood is also collected. A parallel longitudinal study of adolescent adoptive siblings, biologically related siblings, and their parents is also underway. Over 1500 twin families and 350 adoptive and biological sibling families have already entered the longitudinal phase of the study. This article provides an overview of study methods, highlights published findings, and describes procedures in place to foster collaboration with other investigators.

Currently, mapping genes for complex human traits relies on two complementary approaches, linkage and association analyses. Both suffer from several methodological and theoretical limitations, which can considerably increase the type-1 error rate and reduce the power to map human quantitative trait loci (QTL). This review focuses on linkage methods for QTL mapping. It summarizes the most common linkage statistics used, namely Haseman–Elston-based methods, variance components, and statistics that condition on trait values. Methods developed more recently that accommodate the X-chromosome, parental imprinting and allelic association in linkage analysis are also summarized. The type-I error rate and power of these methods are discussed. Finally, rough guidelines are provided to help guide the choice of linkage statistics.

The genetic and environmental impacts on correlations between hearing and cognitive functions have not been well studied. Cognitive function was evaluated by the Montreal Cognitive Assessment (MoCA). Hearing function was assessed by audiometric pure-tone hearing thresholds at different frequencies, including 0.5 kHz, 1 kHz, 2 kHz, 4 kHz, 8 kHz, and 12.5 kHz, with the lower hearing thresholds indicating better hearing function. Cognitive and hearing functions were measured on 379 complete twin pairs (240 monozygotic and 139 dizygotic pairs) with a median age of 50 years (range: 40–80 years). Bivariate twin models were fitted to quantify the genetic and environmental components of the correlations between hearing and cognitive functions. The analysis showed significantly high genetic correlation between 2 kHz of hearing and cognition (rG = −1.00, 95% CI [−1.00, −0.46]) and moderate genetic correlation between 4 kHz of hearing and cognition (rG = −0.62, 95% CI [−1.00, −0.14]). We found no significant genetic correlations between low as well as high frequencies of hearing and cognition. Low to moderate common and unique environmental correlations were shown between low frequencies of hearing and cognition (−0.13 to −0.39) and the common environmental correlation between 8 kHz, one of the high frequencies of hearing, and cognition (−0.22). The middle frequencies of hearing and cognitive functions may have a shared genetic basis. Low frequencies of hearing and cognition may share similar common and unique environmental factors. At 8 kHz, the high frequency of hearing and cognition may share similar common environment. This twin study detected a significant genetic and environmental basis in the phenotype correlation between cognition and hearing, which differed across frequencies.

This population based study compares the rates of multiple births in the 1990s in four hospitals of different socioeconomic levels. It is well known that women from higher socioeconomic groups have easiest access to infertility therapies because of greater financial resources. The hospital of lower socioeconomic level presented multiple birth rates of approximately 8 per thousand during the decade, which may be considered as the natural one. The other three hospitals presented increased rates that were positively correlated to socioeconomic level. This increase occurred mainly due to dizygotic twins and to triplets and was as high as 4.8 per thousand in 1999. Maternal age was also positively correlated to socioeconomic level for singletons as well as for twins. However, during the decade the mean maternal age increased only in the two hospitals with better socioeconomic levels. Gestational order decreased as socioeconomic levels increased, mainly for twins and triplets. The percentage of singletons with low birthweight and very low birthweight decreased as socioeconomic level increased. However, twins presented with an equal distribution in the four hospitals, indicating that better socioeconomic level did not affect the incidence of low birthweight and very low birthweight among twins. Fetal death rate decreased as socioeconomic level increased but twin/singleton fetal death ratio is three times greater in the hospital of higher socioeconomic level suggesting that even in ideal conditions of medical and hospital facilities, the mortality of twins continues to be much higher than that of singletons.

Blood eosinophil count is associated with a variety of common complex outcomes in epidemiological observation. The aim of this study was to explore the causal association between determined blood eosinophil count and 20 common complex outcomes (10 metabolic, 6 cardiac, and 4 pulmonary). Through Mendelian randomization, we investigated genetic evidence for the genetically determined eosinophil in association with each outcomes using individual-level LifeLines cohort data (n = 13,301), where a weighted eosinophil genetic risk score comprising five eosinophil associated variants was created. We further examined the associations of the genetically determined eosinophil with those outcomes using summary statistics obtained from genome-wide association study consortia (6 consortia and 14 outcomes). Blood eosinophil count, by a 1-SD genetically increased, was not statistically associated with common complex outcomes in the LifeLines. Using the summary statistics, we showed that a higher genetically determined eosinophil count had a significant association with lower odds of obesity (odds ratio (OR) 0.81, 95% confidence interval (CI) [0.74, 0.89]) but not with the other traits and diseases. To conclude, an elevated eosinophil count is unlikely to be causally associated to higher risk of metabolic, cardiac, and pulmonary outcomes. Further studies with a stronger genetic risk score for eosinophil count may support these results.

This article discusses findings of two recent studies conducted in collaboration with the East Flanders Prospective Twin Survey in the field of cognitive ability. The first study examined the effect of chorion type on heritability estimates of intelligence in children. The second study investigated the causes of association between child psychopathology and lower cognitive ability. Findings of these studies are discussed in the light of the current view on cognitive ability (or ‘g’) and recommendations for future research are made.

Through its ability to induce the enhanced release and production of cytokines, amyloid-β is responsible for the chronic inflammatory response that contributes to Alzheimer's disease (AD). Determining whether the response of monocytes to amyloid-β stimulation is under genetic control may help understand the basis of why some people are more prone to develop neuronal degeneration than others. In the current study we investigated the heritability of the cytokine (IL-10, IL-6, IL-1β, IL-1ra, TNF-[.alpha]) production capacity upon ex vivo stimulation with amyloid-β in whole blood samples of 222 twins and 85 singleton siblings from 139 extended twin families. It was found that individual differences in amyloid-β-induced cytokine production capacity are to a large extent of genetic origin, with heritability estimates ranging from 55% (IL-1β) to 68% (IL-6). We conclude that genes influencing amyloid-β-induced cytokine response may provide clues to the progression of AD pathology.

Recent Genome-Wide Association Studies (GWAS) have identified four low-penetrance ovarian cancer susceptibility loci. We hypothesized that further moderate- or low-penetrance variants exist among the subset of single-nucleotide polymorphisms (SNPs) not well tagged by the genotyping arrays used in the previous studies, which would account for some of the remaining risk. We therefore conducted a time- and cost-effective stage 1 GWAS on 342 invasive serous cases and 643 controls genotyped on pooled DNA using the high-density Illumina 1M-Duo array. We followed up 20 of the most significantly associated SNPs, which are not well tagged by the lower density arrays used by the published GWAS, and genotyping them on individual DNA. Most of the top 20 SNPs were clearly validated by individually genotyping the samples used in the pools. However, none of the 20 SNPs replicated when tested for association in a much larger stage 2 set of 4,651 cases and 6,966 controls from the Ovarian Cancer Association Consortium. Given that most of the top 20 SNPs from pooling were validated in the same samples by individual genotyping, the lack of replication is likely to be due to the relatively small sample size in our stage 1 GWAS rather than due to problems with the pooling approach. We conclude that there are unlikely to be any moderate or large effects on ovarian cancer risk untagged by less dense arrays. However, our study lacked power to make clear statements on the existence of hitherto untagged small-effect variants.

In the mammary gland, Wnt signals are strongly implicated in initial development of the mammary rudiments and in the ductal branching and alveolar morphogenesis that occurs during pregnancy. Previously, we identified two Wnt signaling pathway-implicated genes, PPP3CA and MARK4, as having a role in more aggressive and potentially metastatic breast tumors. In this study, we examined two SNPs within PPP3CA and MARK4 in an Australian case-control study population for a potential role in human breast cancers. 182 cases and 180 controls were successfully genotyped for the PPP3CA SNP (rs2850328) and 182 cases and 177 controls were successfully genotyped for the MARK4 SNP (rs2395) using High Resolution Melt (HRM) analysis. Genotypes of randomly selected samples for both SNPs were validated by dye terminator sequencing. Chi-square tests were performed to determine any significant differences in the genotype and allele frequencies between the cases and controls. Chi-square analysis showed no statistically significant difference (ρ > .05) for genotype frequencies between cases and controls for rs2850328 (χ2 = 1.2, p = .5476) or rs2395 (χ2 = .3, p = .8608). Similarly, no statistical difference was observed for allele frequencies for rs2850328 (χ2 = .68, p = .4108) or rs2395 (χ2 = .02, p = .893). Even though an association of the polymorphisms rs2850328 and rs2395 and breast cancer was not detected in our case-control study population, other variants within the PPP3CA and MARK4 genes may still be associated with breast cancer, as both genes are implicated with processes involved in the disease as well as their mutual partaking in the Wnt signaling pathway.

Background: Hypospadias is associated with twinning. The incidence of hypospadias in monochorionic and dichorionic male twins is, however, yet to be determined. Methods: All medical records of monochorionic and dichorionic twins admitted to our neonatal nursery between January 2004 and August 2013 were reviewed for the presence of hypospadias. Results: A total of 350 monochorionic and 303 dichorionic male twins were included in the study. The incidence of hypospadias in monochorionic and dichorionic groups was 4% (14/350) and 1% (3/303) (p = .016) respectively. In 11 of the 15 twin couples, hypospadias occurred in the twin with the lowest birth weight. The rate of hypospadias in twin infants small-for-gestational-age group was 10% (6/60) compared with 2% (11/593) in the appropriate-for-gestational-age group (p = .002). In a multivariate analysis, both monochorionicity and small-for-gestational-age were independently associated with hypospadias, odds ratio 4.1 (95% confidence interval (CI): 1.1–14.7) and 6.1 (95% CI: 2.2–17.2) respectively. Conclusions: The incidence of hypospadias is four-fold higher in monochorionic twins compared with dichorionic twins. Hypospadias is also independently associated with small-for-gestational-age.

Aim: In this study, we introduce the first twin study in Turkey, focusing on smoking behavior, and laying the foundation to register all twins born in Turkey for research purposes. Using Turkish twins will contribute to our understanding of health problems in the context of cultural differences. Materials and methods: We assessed 309 twin pairs (339 males and 279 females) aged between 15 and 45 years living in the Kırıkkale and Ankara regions of Turkey, and administered a health and lifestyle interview that included questions about smoking status and smoking history. We analyzed the data using descriptive statistics, t-tests, chi-square tests, and bivariate and multivariate clustered logistic regression. In addition, we fit bivariate Structural Equation Models (SEM) to determine contributions of latent genetic and environmental factors to smoking outcomes in this sample. Results: One hundred seventy-eight participants (28.8%) were identified as smokers, smoking every day for a month or longer, of whom 79.2% were males and 20.8% were females. Mean values for number of cigarettes per day and the Fagerstrom Test of Nicotine Dependence (FTND; Fagerstrom, 1978) score were higher in males than in females, and age of onset was earlier in males. There was a significant positive correlation between the FTND score and number of cigarettes smoked per day, and a significant negative correlation between both variables and age at onset of smoking. Our study showed that gender, presence of a smoking twin in the family, age, alcohol use, marital status, daily sports activities, and feeling moody all played a significant role in smoking behavior among twins. The twin analysis suggested that 79.5% of the liability to FTND was influenced by genetic factors and 20.5% by unique environment, while familial resemblance for smoking initiation was best explained by common environmental factors. Conclusions: Marked differences in the prevalence of smoking behavior in men versus women were observed for the Turkish population. Genetic analyses showed that common environmental factors primarily contributed to smoking initiation, while genetic factors explained a greater proportion of variance in liability to nicotine dependence. Our study shows higher heritability estimate of the FTND scores and higher shared environmental influence on smoking initiation for both males and females than reported in previous studies.

The purpose of this update is to provide the most current information about both the Colorado Adoption Project (CAP) and the Longitudinal Twin Study (LTS) and to introduce the Colorado Adoption/Twin Study of Lifespan behavioral development and cognitive aging (CATSLife), a product of their merger and a unique study of lifespan behavioral development and cognitive aging. The primary objective of CATSLife is to assess the unique saliency of early childhood genetic and environmental factors to adult cognitive maintenance and change, as well as proximal influences and innovations that emerge across development. CATSLife is currently assessing up to 1600 individuals on the cusp of middle age, targeting those between 30 and 40 years of age. The ongoing CATSLife data collection is described as well as the longitudinal data available from the earlier CAP and LTS assessments. We illustrate CATSLife via current projects and publications, highlighting the measurement of genetic, biochemical, social, sociodemographic and environmental indices, including geospatial features, and their impact on cognitive maintenance in middle adulthood. CATSLife provides an unparalleled opportunity to assess prospectively the etiologies of cognitive change and test the saliency of early childhood versus proximal influences on the genesis of cognitive decline.

The objective of this study was to estimate how much of an individual's appreciation of humour is influenced by genetic factors, the shared environment or the individual's unique environment. A population-based classical twin study of 127 pairs of female twins (71 monozygous (MZ) and 56 dizygous (DZ) pairs) aged 20–75 from the St Thomas' UK Adult Twin Registry elicited responses to five ‘Far Side’ Larson cartoons on a scale of 0–10. Within both MZ and DZ twin pairs, the tetrachoric correlations of responses to all five cartoons were significantly greater than zero. Furthermore, the correlations for MZ and DZ twins were of similar magnitude and in some cases the DZ correlation was greater than that of the MZ twins. This pattern of correlations suggests that shared environment rather then genetic effects contributes to cartoon appreciation. Multivariate model-fitting confirmed that these data were best explained by a model that allowed for the contribution of the shared environment and random environmental factors, but not genetic effects. However, there did not appear to be a general humour factor underlying responses to all five cartoons and no effect of age was seen. The shared environment, rather than genetic factors, explains the familial aggregation of humour appreciation as assessed by the specific ‘off the wall’ cognitive type of cartoons used in this study. Twin Research (2000) 3, 17–22.

A new Swedish twin register was created in 1998. All male twins born in Sweden 1973–1979 were identified in the Swedish Medical Birth Register. 3566 twins (1783 pairs) who were alive and residents of Sweden in 1997 were included in the new register. Data on birthweight, birthlength, gestational age, and so forth, were obtained from the Medical Birth Register. Record linkage was effected with the Military Service Conscription Register for the years 1991–1999. Anthropometrical data and information on blood pressure were obtained from this latter source. In 1998 a questionnaire was mailed to all twins in the register. Questions were posed about zygosity, socioeconomic conditions, lifestyle factors (physical activity, smoking habits, etc.), body shape and body size. Complete responses were obtained from 2654 twins (1327 pairs). In 2002 the cohort is being followed-up by a more extensive mailed questionnaire. Data will be collected about socioeconomic conditions, lifestyle, eating behaviour (TFEQ), body size and body shape. In the next few years genomic DNA will also be collected from buccal mucosa (using brush techniques).

Several single nucleotide polymorphisms (SNPs) in candidate genes of DNA repair and hormone pathways have been reported to be associated with endometrial cancer risk. We sought to confirm these associations in two endometrial cancer case-control sample sets and used additional data from an existing genome-wide association study to prioritize an additional SNP for further study. Five SNPs from the CHEK2, MGMT, SULT1E1 and SULT1A1 genes, genotyped in a total of 1597 cases and 1507 controls from two case-control studies, the Australian National Endometrial Cancer Study and the Polish Endometrial Cancer Study, were assessed for association with endometrial cancer risk using logistic regression analysis. Imputed data was drawn for CHEK2 rs8135424 for 666 cases from the Study of Epidemiology and Risk factors in Cancer Heredity study and 5190 controls from the Wellcome Trust Case Control Consortium. We observed no association between SNPs in the MGMT, SULT1E1 and SULT1A1 genes and endometrial cancer risk. The A allele of the rs8135424 CHEK2 SNP was associated with decreased risk of endometrial cancer (adjusted per-allele OR 0.83; 95%CI 0.70-0.98; p = .03) however this finding was opposite to that previously published. Imputed data for CHEK2 rs8135424 supported the direction of effect reported in this study (OR 0.85; 95% CI 0.65–1.10). Previously reported endometrial cancer risk associations with SNPs from in genes involved in estrogen metabolism and DNA repair were not replicated in our larger study population. This study highlights the need for replication of candidate gene SNP studies using large sample groups, to confirm risk associations and better prioritize downstream studies to assess the causal relationship between genetic variants and cancer risk. Our findings suggest that the CHEK2 SNP rs8135424 be prioritized for further study as a genetic factor associated with risk of endometrial cancer.

The aim of the study was to assess, using population-based data, trends and regional variations in multiple births during the period of increasing use and changes in practice patterns for infertility treatments. National data for 24,554,977 births (live births and stillbirths) were used, including 569,423 twins during the period 1972 to 2003, and 14,599 triplets for 1984 to 2003. Statistical analyses included age-adjusted hierarchical logistic regression models for twin births and separate analyses for triple, same-sex, and different-sex twin births. Due to confidentiality considerations, the only variable available for adjustment was maternal age. Regionallevel variations were estimated using median odds ratios based on random-intercept hierarchical logistic regression models. Overall, twin births increased from 18.1 per 1000 births (95% confidence interval [CI] 17.9–18.2) in 1972 to 1975 to 29.9 per 1000 (95% CI 29.7–30.1) in 2000 to 2003. Twin births increased progressively across all regions, whereas triple births reached a peak in the early 1990s and decreased thereafter. Trends for both twin and triple births varied significantly across regions. Both trends and regional variations were greater for different-sex as compared with same-sex twin births. Regional variations in the proportion of multiple births increased in the case of twin births and decreased for triple births. Differences in multiple births at the regional level in France were comparable to country-level differences observed across several western and northern European countries. Regional differences in multiple births need to be monitored and used to inform policies aimed at regulating the use of infertility treatments.

This article analyzes the effect of classroom separation of twins on their cognitive abilities, measured at different ages in Dutch primary education. We use a large longitudinal school-based sample of twins and their classmates. The analysis tries to reduce the bias by unobserved factors due to the nonrandom assignment of twins by taking into account differences in school environment, previous test scores and variation in class assignment between years. We find that classroom separation matters for language in Grade 2. Nonseparated twins score higher on language, and the difference is larger for same-sex pairs. This finding is robust for various methods that take unobserved effects into account. In addition, there is some evidence for higher scores in arithmetic in Grade 2. For the higher grades we find no effect of classroom separation on cognitive ability. In the analysis of the effect of a separation of at least 3 years we find that separation increases language performance between Grade 6 and 8 for opposite-sex pairs.

Twin anemia-polycythemia sequence (TAPS) is a rare condition in monochorionic twin pregnancies. Small intertwin placental vascular communications allow transfusion, which results in a hemoglobin difference in the twins in the absence of oligohydramnios or polyhydramnios. We report here a case of TAPS diagnosed at 17 weeks’ gestation in an obese patient (BMI 42) with a whole anterior placenta. The only possible treatment at this stage of pregnancy was intra-uterine transfusion (IUT), which was repeated weekly until photocoagulation of placental anastomoses was feasible. Fetoscopic laser surgery is the only curative treatment, but is challenging in TAPS because of the absence of polyhydramnios and the presence of minuscule anastomoses. An anterior placenta and high BMI can make the procedure even more challenging. This case report demonstrates that very early and rapidly progressing TAPS with technically complicated conditions (elevated BMI and anterior placenta) can be successfully managed with IUT until laser procedure is achievable.