Human genetics spans every facet of biology from molecular science, through laboratory and clinical practice, to psychology and anthropology. In each of these areas, the history of human genetics has been punctuated by paradigm shifts in knowledge. Each such new concept has been received with skepticism, often with perplexity, and sometimes with frank incredulity. Such comprise the datum milestones along the path leading to our present corpus of genetic knowledge. In parallel to the personal threats to Copernicus and Galileo in the field of astronomy in the 17th century, almost all genetic discoveries of the 19th and 20th centuries were seen as challenges to the received wisdom, and sometimes the social order, of their time and place. Researchers, scientists and clinicians encountering such new and often-heretical paradigm shifts have required considerable resolve to promote and publish their work. Just as in the field of astronomy, new directions in genetics have threatened not only the reputations and sometimes the careers of scientists, but also have been challenges to fundamental religious and sociological beliefs in society more broadly. Examples followed the discovery of biological sexual dimorphism (in plants as well as animals) by Nehemiah Grew (1641–1712). Darwinian evolution, Mendel's First and Second Laws, the existence of mitochondrial genes, apoptosis and its genetic basis, and uniparental disomy are more recent examples. Many of these new revelations, which today have led to the current understanding of fundamental biology, were discovered by individuals working in relative isolation. To promote and publish findings that fundamentally challenge received wisdom continues to require considerable resolve, if not courage. Herein lies a message for all clinicians and researchers.

In order to estimate the influence of genetic and environmental factors on ‘crying without a cause’ and ‘being easily upset’ in 2-year-old children, a large twin study was carried out. Prospective data were available for ~18,000 2-year-old twin pairs from the Netherlands Twin Register. A bivariate genetic analysis was performed using structural equation modeling in the Mx software package. The influence of maternal personality characteristics and demographic and lifestyle factors was tested to identify specific risk factors that may underlie the shared environment of twins. Furthermore, it was tested whether crying without a cause and being easily upset were predictive of later internalizing, externalizing and attention problems. Crying without a cause yielded a heritability estimate of 60% in boys and girls. For easily upset, the heritability was estimated at 43% in boys and 31% in girls. The variance explained by shared environment varied between 35% and 63%. The correlation between crying without a cause and easily upset (r = .36) was explained both by genetic and shared environmental factors. Birth cohort, gestational age, socioeconomic status, parental age, parental smoking behavior and alcohol use during pregnancy did not explain the shared environmental component. Neuroticism of the mother explained a small proportion of the additive genetic, but not of the shared environmental effects for easily upset. Crying without a cause and being easily upset at age 2 were predictive of internalizing, externalizing and attention problems at age 7, with effect sizes of .28–.42. A large influence of shared environmental factors on crying without a cause and easily upset was detected. Although these effects could be specific to these items, we could not explain them by personality characteristics of the mother or by demographic and lifestyle factors, and we recognize that these effects may reflect other maternal characteristics. A substantial influence of genetic factors was found for the two items, which are predictive of later behavioral problems.

Most studies on lung function heritability have been conducted in smokers and non-smokers using cross-sectional study design. Smoking patterns may, however, confound the contribution of genetic factors. We investigated heritability of forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio longitudinally, excluding the effects of smoking. A sample of never smoking female twins (n = 374), aged 63–76 at baseline, answered health questionnaires and attended spirometry in years 2000 and 2003. Bivariate structural equation modeling, restricted to adequate spirometry performances (baseline n = 339, follow-up n = 252), was used to estimate genetic and environmental influences on consecutive measurements of FEV1, FVC, and FEV1/FVC. The best-fitting models included additive genetic and non-shared environmental effects. Heritability estimates of 32% and 36% for FEV1, 41% and 37% for FVC, while 46% and 16% for FEV1/FVC were found at baseline and at follow-up. Genetic correlation between FEV1 and FEV1/FVC heritability estimates approached unity, whereas correlation between FVC estimates was 0.80. Environmental correlations were 0.69 for FEV1, 0.62 for FVC, and 0.07 for FEV1/FVC. In never smokers, additive genetic and non-shared environmental effects explain the inter-individual variations in FEV1, FVC, and FEV1/FVC. One third of the variation in FEV1 and FVC is explained by genetic and two thirds by environmental effects. Between 2000 and 2003, environmental effects on FEV1/FVC changed, and the proportion of variance explained by environmental effects increased remarkably. Genetic effects on FEV1 and FEV1/FVC are common to consecutive measurements, whereas at follow-up, new genetic factors explained 14% of the observed variance in FVC.

Genes in the TGF9 signaling pathway play important roles in the regulation of ovarian follicle growth and ovulation rate. Mutations in three genes in this pathway, growth differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15) and the bone morphogenetic protein receptor B 1 (BMPRB1), influence dizygotic (DZ) twinning rates in sheep. To date, only variants in GDF9 and BMP15, but not their receptors transforming growth factor ß receptor 1 (TGFBR1), bone morphogenetic protein receptor 2 (BMPR2) and BMPR1B, have been investigated with respect to their roles in human DZ twinning. We screened for rare and novel variants in TGFBR1, BMPR2 and BMPR1B in mothers of dizygotic twins (MODZT) from twin-dense families, and assessed association between genotyped and imputed variants and DZ twinning in another large sample of MODZT. Three novel variants were found: a deep intronic variant in BMPR2, and one intronic and one non-synonymous exonic variant in BMPRB1 which would result in the replacement of glutamine by glutamic acid at amino acid position 294 (p.Gln294Glu). None of these variants were predicted to have major impacts on gene function. However, the p.Gln294Glu variant changes the same amino acid as a sheep BMPR1B functional variant and may have functional consequences. Six BMPR1B variants were marginally associated with DZ twinning in the larger case-control sample, but these were no longer significant once multiple testing was taken into account. Our results suggest that variation in the TGF9 signaling pathway type II receptors has limited effects on DZ twinning rates in humans.

microRNAs are small, non-coding RNAs that influence gene expression on a post-transcriptional level. They participate in diverse biological pathways and may act as either tumor suppressor genes or oncogenes. As they may have an effect on thousands of target mRNAs, single-nucleotide polymorphisms in microRNA genes might have major functional consequences, because the microRNA's properties and/or maturation may change. miR-196a has been reported to be aberrantly expressed in breast cancer tissue. Additionally, the SNP rs11614913 in hsa-mir-196a-2 has been found to be associated with breast cancer risk in some studies although not in others. This study evaluated the association between rs11614913 and breast cancer risk in a Caucasian case-control cohort in Queensland, Australia. Results do not support an association of the tested hsa-mir-196a-2 polymorphism with breast cancer susceptibility in this cohort. As there is a discrepancy between our results and previous findings, it is important to assess the role of rs11614913 in breast cancer by further larger studies investigating different ethnic groups.

An evolving hypothesis postulates that melanomas may arise through ‘nevus-associated’ and ‘chronic sun exposure’ pathways. We explored this hypothesis by examining associations between nevus-associated loci and melanoma risk across strata of body site and histological subtype. We genotyped 1028 invasive case patients and 1469 controls for variants in methylthioadenosine phosphorylase (MTAP), phospholipase A2, group VI (PLA2G6), and Interferon regulatory factor 4 (IRF4), and compared allelic frequencies globally and by anatomical site and histological subtype of melanoma. Odds-ratios (ORs) and 95% confidence intervals (CIs) were calculated using classical and multinomial logistic regression models. Among controls, MTAP rs10757257, PLA2G6 rs132985 and IRF4 rs12203592 were the variants most significantly associated with number of nevi. In adjusted models, a significant association was found between MTAP rs10757257 and overall melanoma risk (OR = 1.32, 95% CI = 1.14–1.53), with no evidence of heterogeneity across sites (Phomogeneity =.52). In contrast, MTAP rs10757257 was associated with superficial spreading/nodular melanoma (OR = 1.34, 95% CI = 1.15– 1.57), but not with lentigo maligna melanoma (OR = 0.79, 95% CI = 0.46–1.35) (Phomogeneity =.06), the subtype associated with chronic sun exposure. Melanoma was significantly inversely associated with rs12203592 in children (OR = 0.35, 95% CI = 0.16–0.77) and adolescents (OR = 0.61, 95% CI = 0.42–0.91), but not in adults (Phomogeneity =.0008). Our results suggest that the relationship between MTAP and melanoma is subtype-specific, and that the association between IRF4 and melanoma is more evident for cases with a younger age at onset. These findings lend some support to the ‘divergent pathways’ hypothesis and may provide at least one candidate gene underlying this model. Further studies are warranted to confirm these findings and improve our understanding of these relationships.

We aimed to determine (1) the prevalence of premenstrual syndrome in a sample of twins and (2) the relative contribution of genes and environment in premenstrual syndrome. A group of 193 subjects inclusive of same gender twins (n = 176) and females from opposite sex twin sets (n = 17) entered the study. Heritability analysis used same gender twin data only. The probandwise concordance rate for the presence or absence of premenstrual syndrome was calculated and the heritability of premenstrual syndrome was assessed by a quantitative genetic model fitting approach using MX software. The prevalence of premenstrual syndrome was 43.0% and 46.8% in monozygotic and dizygotic twins, respectively. The probandwise concordance for premenstrual syndrome was higher in monozygotic (0.81) than in dizygotic twins (0.67), indicating a strong genetic effect. Quantitative genetic modeling found that a model comprising of additive genetic (A) and unique environment (E) factors provided the best fit (A: 95%, E: 5%). No association was found between premenstrual symptom and the following variables: belonging to the opposite gender twin set, birth weight, being breast fed and vaccination. These results established a clear genetic influence in premenstrual syndrome.

Sex differences in mental rotation ability have been observed in many countries. A previous study of Finnish participants reported that genetic and environmental influences on mental rotation ability differ between sexes. In this study, we assessed genetic and environmental influences on variance in mental rotation ability in 649 Japanese twins using a mental rotation test. To explain the influence of sex on variance in mental rotation ability, we applied genetic analysis using the sex limitation model. The following two factors explained variance in mental rotation ability: (1) the additive genetic factor, which reflects the accumulated small influence of many genes, and (2) the unique environmental factor, which is a type of environmental factor that differs between co-twins. The shared environmental factor, a type of environmental factor common for co-twins, could not explain the variance in mental rotation ability. Furthermore, the additive genetic factor was the same between sexes (i.e., not qualitative sex differences for the additive genetic factor), indicating that the same genes affect mental rotation ability in both sexes. Despite this observation, the additive genetic influence was greater in males than in females. In contrast, the unique environmental influence was not different between sexes. Considering the current results and those of a previous study, the quantitative sex difference for the additive genetic influences in mental rotation ability may be universal, while the unique environmental differences may depend on the characteristics of specific populations.

Background: There is currently little evidence concerning the impact of the inter-twin relationship on behavioral outcomes and yet the twin relationship is frequently hypothesized to be a unique source of psychopathology in twins. The current study asked whether the inter-twin relationship is a predictor of behavioral difficulties and whether there are zygosity differences in this relationship.

Method: An Australian sample of same sex twins (N = 356, 164 MZ and 192 DZ) was studied in the year prior to school (Time 1) and again in first year of school (Time 2). Associations between twin-relationship and behavior problems were examined via path-analysis, and Satorra-Bentler chi-square difference tests were used to compare twins across zygosity.

Results: Results show that both conflict and lower levels of warmth at Time 1 were predictive of hyperactivity and conduct disorder at Time 2, but they were not associated with emotional difficulties or peer problems. While DZ twins shared less warmth than MZ twins, there were no differences in behavior problems.

Conclusion: Conflict and lower levels of warmth in the inter-twin relationship are associated with hyperactivity and conduct disorder and may serve as important considerations when making decisions regarding class separation at entry to school.

Multiple pregnancies are thought to be associated with a high incidence of perinatal complications such as preterm labor, preeclampsia and low birth weight. But the true mechanisms of these obstetric complications are still uncertain. The components of amniotic fluid reflect the pathophysiology features of the fetus. Amniotic fluid soluble fms-like tyrosine kinase 1(sFLT1), soluble endoglin (sENG), and adiponectin reflect the oxidative stress and pro-inflammatory status and are associated with preeclampsia and fetal growth restriction. We prospectively collected amniotic fluids during amniocentesis from singleton and twin pregnancies. Samples were analyzed for levels of sFLT1, sENG, and adiponectin by enzyme-linked immunosorbent assay. The levels of sENG and sFLT1 were significantly increased in twin pregnancies. Adiponectin was not significantly different between the two groups. These findings would suggest that twin fetuses suffer from more oxidative stress and pro-inflammatory status from the early trimesters.

Objective: To evaluate the perinatal outcome of MC twins with selective IUGR (sIUGR).

Study design: A prospective study, which included three groups of MC twins: Group A, uncomplicated MC twin pregnancies (n = 91); group B, sIUGR with normal umbilical artery Doppler (n = 19); and group C, sIUGR with abnormal (absence or reversed EDV) umbilical artery Doppler (n = 18). The latter were routinely hospitalized in the high-risk ward under strict surveillance.

Results: Neonatal outcome of fetuses complicated with sIUGR and normal Doppler was similar to controls. Neonates born to pregnancies complicated by sIUGR and abnormal Doppler had significantly increased incidence of CNS findings, RDS, NEC, sepsis, and neonatal death compared to controls. Adverse outcome in this group was independently associated only with gestational age at birth.

Conclusion: The perinatal outcomes of MC twins complicated with sIUGR and normal Doppler are similar to uncomplicated MC pregnancies. MC twins with sIUGR and abnormal Doppler have reasonable outcomes, yet significantly more neonatal complications compared to non-complicated MC twins.

To evaluate whether growth discordance is an independent risk factor in the neonatal outcome of the smaller twin, all medical records of twin pregnancies delivered between 26 and 41 weeks during a 5-year period (January 2004–December 2008) were reviewed. Among the 49 selected twins, weight discordance was 15–20% in 7 infants, 21–30% in 16 infants, 31–40% in 16 infants and > 40% in 10 infants. No significant differences between the four groups were found with regards to obstetric complications and neonatal disease. Occurrence of birthweight below the 10th percentile and rate of admission to the neonatal intensive care unit significantly increased as intra-pair birthweight difference increased (p = .03). The > 40% discordant group had a significantly lower gestational age (p = .03), lower birthweight (p = .007) and a significantly higher mortality rate (4/10 versus 3/39 p = .04) in comparison with the other discordant groups. Multiple logistic regression analysis showed that birthweight was the single independent and consistent factor associated with elevated risks of mortality. For every 250 g increase in birthweight, the risk for mortality decreased by about 84% [RR 0.16(CI 0.00-0.70)]. Gestational age was the most reliable predictor for major neonatal complications. For every 1-week increase in gestational age a significant decreased risk for all outcomes was found. Discordance alone should not be considered as a predictor for adverse neonatal outcome. Neonatal outcome in discordant twins appears to be related to gestational age and birthweight rather than to the degree of discordance.

We analyzed the characteristics associated with the growth in height of Japanese triplets from birth to 12 years of age. The study included 376 mothers and their 1,128 triplet children, who were born between 1978 and 2006. Data were collected through a mailed questionnaire sent to the mothers asking for information recorded in medical records. For these births, data on triplets' length and height growth, gestational age, sex, parity, maternal age at delivery, and maternal height were obtained from records in the Maternal and Child Health Handbooks and records in the school which children receive health check-ups. The height deficit of the triplets compared to the general population of Japan remained between 2% and 5% until 12 years of age. Moreover, at 12 years of age, the differences of height between the general population and triplets were approximately -3.6 cm for male and -4.4 cm for female. Maternal height showed the strongest contribution to height of triplets from 6 to 12 years of age. In conclusion, triplets remain shorter than singletons until 12 years of age.

The effect of assisted reproductive technology (ART) and non-ART ovulation stimulation fertility treatment on the number and rate of multiple live births from 1979–2008 in Japan was estimated using two independent data sources, ART statistics and vital statistics. Japanese ART statistics presented by the Japan Society of Obstetrics and Gynecology between 1989 and 2008 were gathered and reanalyzed. The number and rates of ART between 1984 and 1988 were interpolated using an approximation formula, using the values from 1983, when the first ART baby was born in Japan, and the 1989–1992 values. The number of ART multiples between 1979–1982 was set as equal to zero. The minimum (or maximum) number of non-ART iatrogenic multiple births was estimated by subtracting the maximum (or minimum) ART multiples from the total iatrogenic multiples, which was estimated by vital statistics assuming that spontaneous multiple-birth rates according to maternal age class would be constant. There was an overall increase in the non-ART multiple births during the 30-year period, whereas ART multiples tended to increase from 1983 to 2005, and then rapidly decreased thereafter. The number or percentage of ART multiples was almost consistently lower than that of non-ART multiples. The percentage of non-ART multiples (33%) among the total multiples was estimated to be about three times more than the ART multiples (11–12%) in 2008. Given the medical and social impact of multiple births, it is imperative to construct a hospital-based monitoring system for fertility treatments, specially non-ART fertility treatments and multiple births.

In the past 50 years the incidence of multiple pregnancies has increased dramatically due almost exclusively to two factors: delayed childbearing and assisted reproductive techniques. In this paper we analyze the variations in the incidence of multiple gestations in Andalusia, one of the biggest administrative regions in Spain, over the last decade. Assisted reproduction techniques are very often evaluated only in terms of implantation and pregnancy rates per cycle, ignoring everything related to complications of multiple births, prematurity or economic overload. The rate of twins in Andalusia has increased from 10.9 per thousand in 2000 to 16.2 per thousand in 2009. The rate of triplet births has also increased in recent years. After a decline in 2003, motivated by promulgation of the first Human Assisted Reproduction Law, there was an increase after a second law came into effect in 2006. Health care spending attributable to the excess of multiple pregnancies reported in the decade 2000–2010 may have been much higher than €25 million.

Conjoined twins are rare, but craniopagus conjoined twins are rarer still. A pair of four-year-old craniopagus female twins with an unusual brain structure may offer new clues as to how the brain functions. This overview is followed by reviews of recent twin research on mothers of twins, twin transfusion syndrome, twin delivery options and twin literary themes. Relevant topics appearing in the media include twin tennis champions, twins' parallel lives and deaths, a new book for families with twins and a performance about a twin musical legend.