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.

There is evidence that tamoxifen treatment of BRCA1 and BRCA2 carriers for prior breast cancer increases risk of endometrioid subtype endometrial cancer (EC), and suggestive evidence that BRCA1 and BRCA2 mutation carriers may be predisposed to EC in the absence of tamoxifen exposure. We assessed the association of EC with BRCA1 or BRCA2 mutation status in Australasian breast-ovarian families. Report of at least one case of EC was significantly greater in BRCA1-positive families (35/218 (16%); p = .03) and non-significantly greater in BRCA2-positive families (23/189 (12%); p = .6), compared to high-risk breast cancer families without a BRCA1/2 mutation (86/796 (11%)). EC was the first/concurrent cancer for 41% of EC cases with multiple cancer diagnoses from BRCA1/2 families, and early onset for most of these diagnoses. Mutation status was imputed for ungeno-typed individuals from 57 BRCA1/2 pedigrees reporting EC using BRCAPRO. Effects of genotype on EC diagnosis age, and interaction with tamoxifen therapy, were assessed using Cox proportional hazards regression analysis. EC risk was non-significantly marginally greater for BRCA1 carriers (hazard ratio = 1.25, 95%CI = 0.65–2.41), and BRCA2 carriers (HR = 1.12, 95%CI = 0.51–2.45), compared to non-carrier family members. Tamoxifen therapy was highly significantly associated with EC (HR = 6.68, 95%CI = 3.12–15.15; p = 1.7 x 10-6) in BRCA1/2 families, with no evidence for interaction between tamoxifen therapy and BRCA1/2 genotype. Our family-based study supports a 7-fold increase in EC risk with tamoxifen exposure for female family members from BRCA1/2 families. Early onset EC in carriers without tamoxifen use suggests that further study is required to assess association of modest EC risk with BRCA1/2 mutation status alone.

Cardiovascular diseases are the leading cause of death worldwide. Essential hypertension is a major risk factor for the development of other cardiovascular diseases and is caused by a combination of environmental and genetic factors, with up to 50% of blood pressure variance currently attributed to an individual's genetic makeup. By studying genes that cause monogenic forms of hypertension and pathways relevant to blood pressure control, a number of polymorphisms have been identified that increase an individual's risk of developing high blood pressure. We report on candidate gene association studies and genome-wide association studies that have been performed to date in the field of hypertension research. It is becoming clear that for the majority of people there is no single gene polymorphism that causes hypertension, but rather a number of common genetic variants, each having a small effect. Using pharmacogenomics to personalize the treatment of hypertension holds promise for achieving and sustaining normotensive pressures quickly, while minimizing the risk of adverse reactions and unwanted side-effects. This will decrease the risk of stroke and myocardial infarction in individuals and lead to a reduced burden of disease upon society as a whole.

Family history interviews are widely used in psychiatric research, as well as in genetic and twin studies, and provide a way to collect family history information quickly and economically. To obtain a valid assessment of family history, it is important to investigate which family member will be able to provide accurate information. Previous research shows that the validity of family history reporting can be influenced by characteristics of the informant, such as age, gender and personal history of psychiatric disorder. The aim of this study was to investigate the role of a subject's position in a pedigree on the validity of data collection. Family history data on diabetes and psychiatric disorders were collected in three generations of 33 families by interviewing both an index subject (3rd generation) and his or her mother (2nd generation). Mothers were shown to report higher rates of diabetes and psychiatric disorder in the family compared to the index subjects. There was no significant difference in the disease rate reported by male and female index subject. Mothers who experienced a depressive episode indicated significantly more family members as having a psychiatric disorder than mothers who never experienced such an episode. This could be explained by the presence of informant bias, but may also result from the fact that depression is a heritable disorder and is therefore actually more prevalent in these families. Our findings suggest that family interview data should be collected by interviewing subjects who have a central position in the pedigree and can therefore provide information on his/her own generation, the previous and the next. In addition, psychiatric status of the informant should be carefully addressed.

The multiple risk factors for alcohol use (AU) and alcohol use disorders (AUDs) are interrelated through poorly understood pathways, many of which begin in childhood. In this report, the authors seek to develop an empirical, broad-based developmental model for the etiology of AU and AUDs in men. We assessed 15 risk factors in four developmental tiers in 1,794 adult male twins from the Virginia population based twin registry. The best fitting model explained 39% of the variance in late adolescent AU, and 30% of the liability to lifetime symptoms of AUD. AU and AUDs can be best understood as arising from the action and interaction of two pathways reflecting externalizing genetic/temperamental and familial/social factors. Peer group deviance was important in each pathway. Internalizing symptoms played a more minor role. Familial/social factors were especially important influences on AU, while genetic/temperamental factors were more critical for AUDs. We conclude that AU and AUDs in men are complex traits influenced by genetic, family, temperamental, and social factors, acting and interacting over developmental time.

The Child and Adolescent Twin Study in Sweden (CATSS) is an ongoing longitudinal twin study targeting all twins born in Sweden since July 1, 1992. Since 2004, parents of twins are interviewed regarding the children's somatic and mental health and social environment in connection with their 9th or 12th birthdays (CATSS-9/12). By January 2010, 8,610 parental interviews concerning 17,220 twins had been completed, with an overall response rate of 80%. At age 15 (CATSS-15) and 18 (CATSS-18), twins and parents complete questionnaires that, in addition to assessments of somatic and mental health, include measures of personality development and psychosocial adaptation. Twin pairs in CATSS-9/12 with one or both twins screening positive for autism spectrum disorders, attention deficit/hyperactivity disorder, tic disorders, developmental coordination disorder, learning disorders, oppositional defiant disorder, conduct disorder, obsessive–compulsive disorder, and/or eating problems have been followed with in-depth questionnaires on family, social environment and personality, and subsequently by clinical assessments at age 15 together with randomly selected population controls, including 195 clinically assessed twin pairs from the first 2 year cohorts (CATSS-15/DOGSS). This article describes the cohorts and study groups, data collection, and measures used. Prevalences, distributions, heritability estimates, ages at onset, and sex differences of mental health problems in the CATSS-9/12, that were analyzed and found to be overall comparable to those of other clinical and epidemiological studies. The CATSS study has the potential of answering important questions on the etiology of childhood mental health problems and their role in the development of later adjustment problems.

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.

In twin pregnancy studies, molecular genetic techniques have rarely been used to determine zygosity, despite their known precision and accuracy. The present work aimed to assess the power of discrimination in zygosity assessment, using a set of microsatellite markers that were routinely used for aneuploidy screening by multiplex-PCR in a prenatal context. Rapid aneuploidy screening using a group of 20 microsatellite markers (STRs) located on chromosomes 13, 18, 21 and X has been performed in our lab for over 10 years, with a total of approximately 1,500 samples studied to date. A retrospective analysis of the 257 prenatal samples from multiple pregnancies was carried out. A subset of 14 cases presenting theoretical monozygosity were re-evaluated by the use of biostatistics tools accessed via the ZygProb website. Further monozygosity determination relative to dizygosity was calculated, given an estimated overall error value of 0.093%. The results show that monozygosity had been correctly determined in all our previously studied twins. This work demonstrates that accurate zygosity assessment can be achieved with the same STRs applied in aneuploidy screening with a high power of discrimination and a matching probability of over 99.999999%.

We explored the comorbidity between panic attacks (PA), whose symptoms can include gastrointestinal discomfort, and gastrointestinal disorders (GD). Structural equation modeling was used to analyze data from 1,874 MZ and 1,498 DZ male–male twin pairs from the Vietnam Era Twin Registry. PA and GD were associated (relative risk for GD = 2). The percentage of liability due to genetic factors was estimated to be 37% for PA and 31% for GD. There was significant correlation between the genetic risk factors for PA and GD (estimated r = .55, 95% CI of 34% to 82%) and no evidence of correlation between the environmental causes of PA and GD. Therefore, PA and GD comorbidity can be explained by overlapping genetic factors and not overlapping environmental factors. Although these data cannot identify a biological pathway for such a shared liability, it suggests the presence of GD may be informative for genetic studies of panic.

The current article examines the assumptions of the MZ co-twin control method that has been applied in attempts to gain more accurate estimates of the returns to education by naturally ‘controlling’ for individual differences on which MZ twins are matched. The current study examined 1738 MZ and 926 DZ twins from Minnesota, including 133 pairs of MZ and 101 pairs of DZ twins discordant for university attendance. They were assessed prospectively on personality, intelligence, GPA, and academic motivation; a subset also has reported income at age 29. MZ twins discordant for university attendance differed significantly and prospectively on verbal IQ, personality traits, and GPA. While MZ co-twin control studies can provide more accurate estimates of the returns to education than analyses of single individuals, these studies do not entirely obviate the need to control for differences between university students and non-students that predate university attendance and might account for income differentials and even non-monetary outcomes.

The longitudinal stability of IQ is well-documented as is its increasing heritability with age. In a longitudinal twin study, we addressed the question to what extent heritability and stability differ for full scale (FSIQ), verbal (VIQ), and performance IQ (PIQ) in childhood (age 9–11 years), and early adolescence (age 12–14 years). Genetic and environmental influences and correlations over time were evaluated in an extended twin design, including Dutch twins and their siblings. Intelligence was measured by the Wechsler Intelligence Scale for children — Third version (WISC III). Heritability in childhood was 34% for FSIQ, 37% for VIQ, and 64% for PIQ, and increased up to 65%, 51%, and 72% in early adolescence. The influence of common environment decreased between childhood and early adolescence from explaining 43% of the phenotypic variance for FSIQ to 18% and from 42% for VIQ to 26%. For PIQ common environmental influences did not play a role, either in childhood or in early adolescence. The stability in FSIQ and VIQ across the 3-year interval (rp) was .72 for both measures and was explained by genetic and common environmental correlations across time (FSIQ, rg = .96, rc = 1.0; VIQ, rg =.78, rc = 1.0). Stability of PIQ (rp =.56) was lower and was explained by genetic influences (rg = .90). These results confirm the robust findings of increased heritability of general cognitive abilities during the transition from childhood to adolescence. Interestingly, results for PIQ differ from those for FSIQ and VIQ, in that no significant contribution of environment shared by siblings from the same family was detected.

For decades the relationships of twinning and alterations in body patterning, such as laterality and asymmetry, have been investigated. However, the tools to define and quantify these relationships have been limited and the majority of these studies have relied on associations with subjectively defined phenotypes. The emerging technologies of 3-dimensional (3D) facial scanning and geometric morphometrics are providing the means to establish objective criteria, including measures of asymmetry, which can be used for phenotypic classification and investigations. Additionally, advances in molecular epigenetics provide new opportunities for novel investigations of mechanisms central to early developmental processes, twinning and related phenotypes. We review the evidence for overlapping etiologies of twinning, asymmetry and selected monogenic and complex diseases, and we suggest that the combination of epigenetic investigations with detailed and objective phenotyping, utilizing 3D facial analysis tools, can reveal insights into the genesis of these phenomena.

To determine the relationship between the genetic and environmental risk factors for externalizing psychopathology and mental wellbeing, we examined detailed measures of emotional, social and psychological wellbeing, and a history of alcohol-related problems and smoking behavior in the last year in 1,386 individual twins from same-sex pairs from the MIDUS national US sample assessed in 1995. Cholesky decomposition analyses were performed withthe Mx program. The best fit model contained one highly heritable common externalizing psychopathology factor for both substance use/abuse measures, and one strongly heritable common factor for the three wellbeing measures. Genetic and environmental risk factors for externalizing psychopathology were both negatively associated with levels of mental wellbeing and accounted for, respectively, 7% and 21% of its genetic and environmental influences. Adding internalizing psychopathology assessed in the last year to the model, genetic risk factors unique for externalizing psychopathology were now positively related to levels of mental wellbeing, although accounting for only 5% of the genetic variance. Environmental risk factors unique to externalizing psychopathology continued to be negatively associated with mental wellbeing, accounting for 26% of the environmental variance. When both internalizing psychopathology and externalizing psychopathology are associated with mental wellbeing, the strongest risk factors for low mental wellbeing are genetic factors that impact on both internalizing psychopathology and externalizing psychopathology, and environmental factors unique to externalizing psychopathology. In this model, genetic risk factors for externalizing psychopathology predict, albeit weakly, higher levels of mental wellbeing.

Physical activity is influenced by genetic factors whose expression may change with age. We employed an extension to the classical twin model that allows a modifier variable, age, to interact with the effects of the latent genetic and environmental factors. The model was applied to self-reported data from twins aged 19 to 50 from seven countries that collaborated in the GenomEUtwin project: Australia, Denmark, Finland, Norway, Netherlands, Sweden and United Kingdom. Results confirmed the importance of genetic influences on physical activity in all countries and showed an age-related decrease in heritability for 4 countries. In the other three countries age did not interact with heritability but those samples were smaller or had a more restricted age range. Effects of shared environment were absent, except in older Swedish participants. The study confirms the importance of taking age effects into account when exploring the genetic and environmental contribution to physical activity. It also suggests that the power of genome-wide association studies to identify the genetic variants contributing to physical activity may be larger in young adult cohorts.

Renal cell carcinoma is an important clinical disease with poorly understood etiology. ELF5 is an epithelial-specific member of the Ets family of transcription factors, characterized by the 80 amino acid Ets domain that binds the purine-rich GGAA/T Ets motif found in the promoter regions of a variety of genes. Since ELF5 is highly expressed in kidney and has been postulated to function as a tumor suppressor, at least in the context of the breast, we investigated its role in kidney cancer. In renal cell carcinoma ELF5 expression was consistently decreased in tumor samples versus normal. ELF5 mRNA was decreased in 94% of lesions tested and ELF5 protein was undetectable in 40/40 kidney-derived carcinomas. Re-expression of the ELF5 gene in 786-O renal carcinoma cells suppressed their tumorigenic capacity in vitro and in vivo. This work is the first to suggest that ELF5 has tumor suppressor activity in the kidney.

A set of 10 SNPs associated with reading ability in 7-year-olds was reported based on initial pooled analyses of 100K SNP chip data, with follow-up testing stages using pooling and individual testing. Here we examine this association in an adolescent population sample of Australian twins and siblings (N = 1177) aged 12 to 25 years. One (rs1842129) of the 10 SNPs approached significance (P = .05) but no support was found for the remaining 9 SNPs or the SNP set itself. Results indicate that these SNPs are not associated with reading ability in an Australian population. The results are interpreted as supporting use of much larger SNP sets in common disorders where effects are small.

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.

Myasthenia gravis (MG) is an autoimmune disorder in which patients experience muscular fatigability due to the presence of anti-acetylcholine receptor (AChR) antibodies which inhibit signal transduction across the neuro-muscular junction. Like all complex disorders, disease is caused by an interaction between genetic and environmental factors. Although several genes have been identified which appear to be associated with MG, both classic twin studies and current multi-gene models are insufficient to explain either disease pathogenesis or inheritance. We examined the literature on MG to determine both mono- and dizygotic twin concordance rates, and used this data to (1) estimate the proportion of the population with underlying genetic predisposition to MG and the frequency of the environmental component and (2) derive the number of inherited genetic regions that are required to confer predisposition to MG. Using a MZ twin concordance rate of 35.5%, and a dizygotic rate of approximately 4–5% (based on family data), the probability of encountering environmental components necessary to develop MG in an individual with genetic predisposition is approximately 52.4%, making the frequency of predisposition (1:5240) roughly twice the rate of incidence. Furthermore, the number of genetic regions co-inherited between affected individuals is between two and four, which may be large haplotypes with interacting activity. Determining these haplotypes, by fully sequencing associated regions in cases and controls to identify mutations present, may therefore be a practically step toward the understanding of complex disease.

There is substantial evidence suggesting a role for hormone-regulated kallikrein-related peptidases (KLKs) in carcinogenesis and tumour metastasis. KLKs are considered to have potential as prognostic biomarkers for hormone dependent cancers, particularly ovarian cancer. The purpose of this study was to evaluate the association between Kallikrein-related peptidase 3 (KLK3) gene single nucleotide polymorphisms (SNPs) located in hormone response elements and ovarian cancer survival. DNA samples were analyzed from 304 Australian women diagnosed with epithelial ovarian cancer. The KLK3 rs266882 and rs11084033 SNPs were genotyped by the Sequenom iPLEX Mass Array platform. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression models. An association was observed with ovarian cancer survival for homozygote carriers of the rare allele of rs11084033 (adjusted HR 2.12, 95% CI 1.08–4.15). This finding is consistent with bioinformatic analysis predicting the rs11084033 rare allele to be responsible for the loss of a confirmed androgen response element, and with published expression data suggesting that aggressive ovarian cancers show decreased KLK3 tumor expression. The rs11084033 has potential prognostic significance in ovarian cancer. However, this finding requires replication, and further investigation regarding the functional significance of rs11084033 and correlated SNPs.

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.