Lack of reproducibility of resting-state functional MRI findings in migraine with aura.

BACKGROUND: Several studies have applied resting-state functional MRI to examine whether functional brain connectivity is altered in migraine with aura patients. These studies had multiple limitations, including small sample sizes, and reported conflicting results. Here, we performed a large, cross-sectional brain imaging study to reproduce previous findings. METHODS: We recruited women aged 30-60 years from the nationwide Danish Twin Registry. Resting-state functional MRI of women with migraine with aura, their co-twins, and unrelated migraine-free twins was performed at a single centre. We carried out an extensive series of brain connectivity data analyses. Patients were compared to migraine-free controls and to co-twins. RESULTS: Comparisons were based on data from 160 patients, 30 co-twins, and 136 controls. Patients were similar to controls with regard to age, and several lifestyle characteristics. We replicated clear effects of age on resting-state networks. In contrast, we failed to detect any differences, and to replicate previously reported differences, in functional connectivity between migraine patients with aura and non-migraine controls or their co-twins in any of the analyses. CONCLUSION: Given the large sample size and the unbiased population-based design of our study, we conclude that women with migraine with aura have normal resting-state brain connectivity outside of migraine attacks.

Changing genetic architecture of body mass index from infancy to early adulthood: an individual based pooled analysis of 25 twin cohorts.

BACKGROUND: Body mass index (BMI) shows strong continuity over childhood and adolescence and high childhood BMI is the strongest predictor of adult obesity. Genetic factors strongly contribute to this continuity, but it is still poorly known how their contribution changes over childhood and adolescence. Thus, we used the genetic twin design to estimate the genetic correlations of BMI from infancy to adulthood and compared them to the genetic correlations of height. METHODS: We pooled individual level data from 25 longitudinal twin cohorts including 38,530 complete twin pairs and having 283,766 longitudinal height and weight measures. The data were analyzed using Cholesky decomposition offering genetic and environmental correlations of BMI and height between all age combinations from 1 to 19 years of age. RESULTS: The genetic correlations of BMI and height were stronger than the trait correlations. For BMI, we found that genetic correlations decreased as the age between the assessments increased, a trend that was especially visible from early to middle childhood. In contrast, for height, the genetic correlations were strong between all ages. Age-to-age correlations between environmental factors shared by co-twins were found for BMI in early childhood but disappeared altogether by middle childhood. For height, shared environmental correlations persisted from infancy to adulthood. CONCLUSIONS: Our results suggest that the genes affecting BMI change over childhood and adolescence leading to decreasing age-to-age genetic correlations. This change is especially visible from early to middle childhood indicating that new genetic factors start to affect BMI in middle childhood. Identifying mediating pathways of these genetic factors can open possibilities for interventions, especially for those children with high genetic predisposition to adult obesity.

Altered Antibody Response to Epstein-Barr Virus in Patients With Rheumatoid Arthritis and Healthy Subjects Predisposed to the Disease. A Twin Study.

Objectives: To study Epstein-Barr virus (EBV) antibody patterns in twin individuals with rheumatoid arthritis (RA) and their healthy co-twins, and to determine the heritability of antibody responses against the EBV encoded EBNA1 protein. Methods: Isotypes of EBNA1 antibodies were measured in 137 RA affected- and 150 healthy twin pairs. We estimated the effect of RA and RA predisposition, anti-citrullinated antibodies (ACPA), IgM rheumatoid factor (RF), the shared epitope (SE) and the PTPN22-T allele (PTPN22) on the level of EBNA1 antibodies. We also determined the heritability of EBNA1 antibody levels. Results: IgA-EBNA1 antibody levels were increased in twins from RA discordant twin pairs irrespective of RA, ACPA or IgM-RF status. The IgG-EBNA1 antibody level was elevated in healthy co-twins from RA discordant twin pairs but not in RA affected twins. The IgM-EBNA1 antibody level was elevated in both RA twins and their healthy co-twins. The effect of RA on the IgA-EBNA1 antibody level was reversed when SE was present and with no effect of PTPN22. The heritability of IgA-, IgG- and IgM-EBNA1 antibody level was 40.6, 65.5, and 54.3%, with no effect of environment shared by the twins. Conclusion: EBNA1 antibody levels are distinctively different between patients with RA and healthy subjects but also between relatives of RA strongly predisposed to RA and healthy subjects. The high level of IgA EBNA1 antibodies associated with RA and a family predisposition to RA is attributable to both genetics incl. the shared epitope and environmental variation.

Disentangling the relationship between bone turnover and glucose homeostasis: A prospective, population-based twin study.

BACKGROUND: Biochemical markers of bone turnover are lower in patients with type 2 diabetes, which may be explained by genetic variants being associated with type 2 diabetes and bone turnover as well as environmental factors. We hypothesized that bone turnover markers associate with and predict changes in glucose homeostasis after control for genetics and shared environment. METHODS: 1071 healthy, non-diabetic (at baseline, 1997-2000) adult mono- and dizygotic twins participating in the prospective study GEMINAKAR were reassessed between 2010 and 2012 with clinical evaluation, biochemical tests and oral glucose tolerance test. Fasting bone turnover markers (CTX, P1NP and osteocalcin) were measured. The association between bone turnover, glucose homeostasis and the ability of bone turnover markers to predict changes in glucose homeostasis were assessed in cross-sectional and longitudinal analyses. Analyses were performed both at an individual level and adjusted for shared environmental and genetic factors. RESULTS: Glucose levels increased with age, and 33 (3%) participants had developed type 2 diabetes at follow-up. In women, bone turnover markers increased with age, whereas for men only osteocalcin increased with age. Bone turnover markers were not associated with fasting glucose, insulin, or HOMA-IR at baseline or follow-up before or after adjustment for age, sex, BMI, smoking, and use of medication at baseline. Variation in bone turnover markers was mainly explained by unique environmental factors, 70%, 70% and 55% for CTX, P1NP and osteocalcin, respectively, whereas additive genetic factors explained 7%, 13% and 45% of the variation in CTX, P1NP and osteocalcin. CONCLUSIONS: Bone turnover markers were not associated with baseline plasma glucose levels and did not predict changes in glucose homeostasis. Variation in bone turnover markers is mainly explained by environmental factors, however, compared to CTX and P1NP, genetic factors have a larger impact on osteocalcin levels.

Inverse Cross-sectional and Longitudinal Relationships between Diabetic Retinopathy and Obstructive Sleep Apnea in Type 2 Diabetes: Results from a National Screening Program.

Purpose: In previous smaller studies, associations were demonstrated between diabetic retinopathy (DR) and obstructive sleep apnea (OSA), but longitudinal relationships have not been evaluated in larger cohorts. The aim of the present study was to assess the cross-sectional and prospective associations between DR and OSA in a national cohort of patients with type 2 diabetes. Design: Cross-sectional and 5-year longitudinal registry-based cohort study. Participants: For cases, we included 153 238 patients with type 2 diabetes who had attended diabetic eye screening and were registered in the Danish Registry of Diabetic Retinopathy (DiaBase). Each of these were matched by 5 control participants without diabetes of the same age and gender (n = 746 148). Methods: Exposure and outcome data as well as systemic morbidity and use of medications were identified in national registers, including the DiaBase, the Danish National Patient Register, the Danish National Prescription Registry, and the Danish Civil Registration System. The index date was defined as the date of the first DR screening registered in DiaBase. Main Outcome Measures: Exposure was defined as present and level-specific DR, and main outcomes were crude, age- and gender-adjusted, and multivariable adjusted odds ratios (ORs) for prevalent OSA as well as hazard ratios (HR) for 5-year incident OSA and DR. Results: Patients with type 2 diabetes independently were more likely to have prevalent OSA (OR, 2.01; 95% confidence interval [CI], 1.95-2.08) and to develop OSA within 5 years (HR, 1.55; 95% CI, 1.46-1.64). Patients with type 2 diabetes and DR at baseline were less likely to have prevalent OSA (OR, 0.57; 95% CI, 0.52-0.62) or to demonstrate incident OSA (HR, 0.86; 95% CI, 0.74-0.99). Likewise, patients with OSA had a lower risk to develop DR (HR, 0.83; 95% CI, 0.74-0.92). Conclusions: In a registry-based national cohort study, patients with type 2 diabetes had a higher risk of OSA. However, a 43% decreased risk of prevalent OSA was demonstrated in patients with DR, and prospectively, OSA and DR both were related inversely with each other.

Heritability of Curve Patterns in Oral Glucose Tolerance Test.

Type 2 diabetes, which is caused by both genetic and environmental factors, may be diagnosed using the oral glucose tolerance test (OGTT). Recent studies demonstrated specific patterns in glucose curves during OGTT associated with cardiometabolic risk profiles. As the relative contribution of genetic and environmental influences on glucose curve patterns is unknown, we aimed to investigate the heritability of these patterns. We studied twins from the Danish GEMINAKAR cohort aged 18-67 years and free from diabetes at baseline during 1997-2000; glucose concentrations were measured three times during a 2-h OGTT. Heterogeneity of the glucose response during OGTT was examined with latent class mixed-effects models, evaluating goodness of fit by Bayes information criterion. The genetic influence on curve patterns was estimated using quantitative genetic modeling based on linear structural equations. Overall, 1455 twins (41% monozygotic) had valid glucose concentrations measured from the OGTT, and four latent classes with different glucose response patterns were identified. Statistical modeling demonstrated genetic influence for belonging to a specific class or not, with heritability estimated to be between 45% and 67%. During ∼12 years of follow-up, the four classes were each associated with different incidence of type 2 diabetes. Hence, glucose response curve patterns associated with type 2 diabetes risk appear to be moderately to highly heritable.

Epidemiology of neuromyelitis optica spectrum disorder in Denmark (1998-2008, 2007-2014).

Epidemiological studies of the uncommon disorder neuromyelitis optica spectrum disorder (NMOSD) may be difficult to interpret because of the evolving nature of diagnostic criteria, differences in the definition and accuracy of NMOSD diagnosis, the completeness of case ascertainment, and variability in assays for the disease-specific biomarker aquaporin-4 (AQP4)-IgG. A sub-group of patients with the clinical syndrome NMOSD lack detectable AQP4-IgG and in these cases an accurate diagnosis requires precise diagnostic algorithms and longitudinal follow-up. Consecutive sets of criteria for NMO/NMOSD have been introduced during the two last decades. Such criteria need validation in different populations. Detection of other autoantibodies, such as IgG specific for myelin oligodendrocyte glycoprotein or for glial fibrillary acidic protein in a sub-group of AQP4-IgG-negative NMOSD patients, has improved over the past decade and may lead to overlap of the clinical syndromes/phenotypes. This review begins by summarizing current knowledge on the widening clinical spectrum of NMOSD. Subsequently, we describe two epidemiological studies from Denmark carried out in two different decades (1998-2008 and 2007-2014) and comment on the differences in study design, patient ascertainment, and interpretation of results. These factors may explain some of the observed differences, reflecting the complexity and providing a clear example of this development.

Surfactant protein-D, a potential mediator of inflammation in axial spondyloarthritis.

Objectives: Surfactant protein-D (SP-D), an innate immune defence molecule of the collectin family, is expressed in lungs and additional extrapulmonary epithelia. SP-D has immune modulatory and anti-microbial effects depending on its oligomerization. The ratio of high molecular weight (HMW): low molecular weight (LMW) SP-D in serum is mainly determined by the Met11Thr polymorphism (SNP rs721917). We aimed to study the SP-D serum level and the molecular size distribution in patients with untreated axial spondyloarthritis (axSpA) as compared with control subjects. Methods: Thirty-four patients with disease modifier untreated axSpA according to the ASAS criteria, age 19-63 years, disease duration 3.9 (2.2-5.6) years were included. Demographics, smoking habits, HLA-B27 status, ASDAS, BASDAI, BASFI, BASMI and visual analogue scale scores were recorded. SP-D in serum was measured by ELISA. DNA was isolated from whole blood and single nucleotide polymorphism rs721917 was genotyped. SP-D molecular size distribution was determined using gel filtration chromatography. Results: SP-D in serum did not differ between patients with axSpA and healthy controls, 1177 (869, 1536) vs 910 (494, 1682) (P = 0.35) and SP-D did not correlate with disease activity. However, the HMW/LMW ratio of SP-D in serum was significantly lower in axSpA, 0.38 (0.18, 0.53) compared with controls 1.49 (0.37, 3.24) when adjusting for the Met11Thr polymorphism, gender, age, BMI and smoking (P = 0.0004). There was no correlation between HMW/LMW ratio and CRP or composite diseases outcome measures. Conclusion: We suggest that predominance of LMW oligomeric variants of SP-D may enhance local or systemic inflammatory responses in axSpA.

Differences in genetic and environmental variation in adult BMI by sex, age, time period, and region: an individual-based pooled analysis of 40 twin cohorts.

Background: Genes and the environment contribute to variation in adult body mass index [BMI (in kg/m2)], but factors modifying these variance components are poorly understood.Objective: We analyzed genetic and environmental variation in BMI between men and women from young adulthood to old age from the 1940s to the 2000s and between cultural-geographic regions representing high (North America and Australia), moderate (Europe), and low (East Asia) prevalence of obesity.Design: We used genetic structural equation modeling to analyze BMI in twins ≥20 y of age from 40 cohorts representing 20 countries (140,379 complete twin pairs).Results: The heritability of BMI decreased from 0.77 (95% CI: 0.77, 0.78) and 0.75 (95% CI: 0.74, 0.75) in men and women 20-29 y of age to 0.57 (95% CI: 0.54, 0.60) and 0.59 (95% CI: 0.53, 0.65) in men 70-79 y of age and women 80 y of age, respectively. The relative influence of unique environmental factors correspondingly increased. Differences in the sets of genes affecting BMI in men and women increased from 20-29 to 60-69 y of age. Mean BMI and variances in BMI increased from the 1940s to the 2000s and were greatest in North America and Australia, followed by Europe and East Asia. However, heritability estimates were largely similar over measurement years and between regions. There was no evidence of environmental factors shared by co-twins affecting BMI.Conclusions: The heritability of BMI decreased and differences in the sets of genes affecting BMI in men and women increased from young adulthood to old age. The heritability of BMI was largely similar between cultural-geographic regions and measurement years, despite large differences in mean BMI and variances in BMI. Our results show a strong influence of genetic factors on BMI, especially in early adulthood, regardless of the obesity level in the population.

Does the sex of one's co-twin affect height and BMI in adulthood? A study of dizygotic adult twins from 31 cohorts.

BACKGROUND: The comparison of traits in twins from opposite-sex (OS) and same-sex (SS) dizygotic twin pairs is considered a proxy measure of prenatal hormone exposure. To examine possible prenatal hormonal influences on anthropometric traits, we compared mean height, body mass index (BMI), and the prevalence of being overweight or obese between men and women from OS and SS dizygotic twin pairs. METHODS: The data were derived from the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) database, and included 68,494 SS and 53,808 OS dizygotic twin individuals above the age of 20 years from 31 twin cohorts representing 19 countries. Zygosity was determined by questionnaires or DNA genotyping depending on the study. Multiple regression and logistic regression models adjusted for cohort, age, and birth year with the twin type as a predictor were carried out to compare height and BMI in twins from OS pairs with those from SS pairs and to calculate the adjusted odds ratios and 95% confidence intervals for being overweight or obese. RESULTS: OS females were, on average, 0.31 cm (95% confidence interval (CI) 0.20, 0.41) taller than SS females. OS males were also, on average, taller than SS males, but this difference was only 0.14 cm (95% CI 0.02, 0.27). Mean BMI and the prevalence of overweight or obesity did not differ between males and females from SS and OS twin pairs. The statistically significant differences between OS and SS twins for height were small and appeared to reflect our large sample size rather than meaningful differences of public health relevance. CONCLUSIONS: We found no evidence to support the hypothesis that prenatal hormonal exposure or postnatal socialization (i.e., having grown up with a twin of the opposite sex) has a major impact on height and BMI in adulthood.

Incidence of Chronic Persistent Rheumatoid Arthritis and the Impact of Smoking: A Historical Twin Cohort Study.

OBJECTIVE: To assess the incidence of chronic persistent rheumatoid arthritis (RA) in a population-based cohort of twins and to determine the impact of smoking. METHODS: In a historical cohort study on twins born in 1920 to 1982, we identified 157 cases of RA among 45,280 responders (response rate 80%). Information on smoking was obtained by questionnaire and interview. A mixed-effects Poisson regression model was used to estimate incidence rate ratios with age, sex, smoking duration, and smoking intensity as covariates. We used the SplitLexis procedure in the Epi R package to study a possible effect of period or cohort in addition to age on the variation of the incidence. RESULTS: The annual incidence of chronic persistent RA was 18.8 per 100,000 person-years, ages 15-73 years (females 25.2, males 12.0), increasing with age to a maximum at age 60 years in females and age 70 years in males. The incidence rate ratio among ever-smoking patients was 1.96 (95% confidence interval [95% CI] 1.43-3.76), 1.93 (95% CI 1.00-3.7) after 30 pack-years, and 1.034 (P < 0.001) per year of smoking, implying a doubling of risk after 20 years regardless of sex and smoking intensity. We did not detect significant period or cohort effects. CONCLUSION: The incidence of chronic persistent RA is lower than the incidence figures reported in inception cohorts. Smoking duration, but not intensity, doubled the risk of RA after 20 years of smoking in both sexes.

Genetic and environmental influences on adult human height across birth cohorts from 1886 to 1994.

Human height variation is determined by genetic and environmental factors, but it remains unclear whether their influences differ across birth-year cohorts. We conducted an individual-based pooled analysis of 40 twin cohorts including 143,390 complete twin pairs born 1886-1994. Although genetic variance showed a generally increasing trend across the birth-year cohorts, heritability estimates (0.69-0.84 in men and 0.53-0.78 in women) did not present any clear pattern of secular changes. Comparing geographic-cultural regions (Europe, North America and Australia, and East Asia), total height variance was greatest in North America and Australia and lowest in East Asia, but no clear pattern in the heritability estimates across the birth-year cohorts emerged. Our findings do not support the hypothesis that heritability of height is lower in populations with low living standards than in affluent populations, nor that heritability of height will increase within a population as living standards improve.

Genetic and environmental effects on body mass index from infancy to the onset of adulthood: an individual-based pooled analysis of 45 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) study.

BACKGROUND: Both genetic and environmental factors are known to affect body mass index (BMI), but detailed understanding of how their effects differ during childhood and adolescence is lacking. OBJECTIVES: We analyzed the genetic and environmental contributions to BMI variation from infancy to early adulthood and the ways they differ by sex and geographic regions representing high (North America and Australia), moderate (Europe), and low levels (East Asia) of obesogenic environments. DESIGN: Data were available for 87,782 complete twin pairs from 0.5 to 19.5 y of age from 45 cohorts. Analyses were based on 383,092 BMI measurements. Variation in BMI was decomposed into genetic and environmental components through genetic structural equation modeling. RESULTS: The variance of BMI increased from 5 y of age along with increasing mean BMI. The proportion of BMI variation explained by additive genetic factors was lowest at 4 y of age in boys (a(2) = 0.42) and girls (a(2) = 0.41) and then generally increased to 0.75 in both sexes at 19 y of age. This was because of a stronger influence of environmental factors shared by co-twins in midchildhood. After 15 y of age, the effect of shared environment was not observed. The sex-specific expression of genetic factors was seen in infancy but was most prominent at 13 y of age and older. The variance of BMI was highest in North America and Australia and lowest in East Asia, but the relative proportion of genetic variation to total variation remained roughly similar across different regions. CONCLUSIONS: Environmental factors shared by co-twins affect BMI in childhood, but little evidence for their contribution was found in late adolescence. Our results suggest that genetic factors play a major role in the variation of BMI in adolescence among populations of different ethnicities exposed to different environmental factors related to obesity.

Concordance Rates of Adolescent Idiopathic Scoliosis in a Danish Twin Population.

STUDY DESIGN: Clinical, radiological, and genetic determination of zygosity of twin pairs from the Danish Twin Registry who self-reported having adolescent idiopathic scoliosis (AIS). OBJECTIVE: To establish concordance rates of AIS. SUMMARY OF BACKGROUND DATA: The etiology of and the true mode of inheritance of AIS remain unclear. Studies on concordance in twin pairs provide a basis for analyzing the influence of genetic versus environmental factors. In 2007, using self-report of AIS from the Danish Twin Registry, concordance rates of 0.13 in monozygotic twins and 0.00 in dizygotic twins were reported. METHODS: All 46,418 twins registered in the Danish Twin Registry born from 1931 to 1982 were sent a survey, which included questions about scoliosis. The survey was returned by 34,944 individuals (75.3%) representing 23,204 pairs. From the present study, 548 individuals representing 274 complete twin pairs in which at least one twin self-reported having scoliosis were invited to a clinical and radiological examination. Zygosity was established by genetic testing. RESULTS: A total of 182 individuals (33.2%) of the original cohort agreed to participate, 128 of whom had scoliosis by self-report. There were 91 twin pairs, in which one or both twins had reported scoliosis and 36 individuals whose twin did not want to participate. Only 35 (27%) of the 128 participants with self-reported scoliosis had a clinically and radiologically confirmed curve. Calculating concordance in twins with Cobb angles greater than 10°, we found that the pairwise concordance rate was 0.4 (0.10-0.70) for monozygotic and 0.05 (-0.05-0.15) for dizygotic twins, P = 0.05, probandwise concordance was 0.45 (0.16-0.74) for monozygotic and 0.1 (-0.03-0.23) for dizygotic pairs. CONCLUSION: Concordance rates in a Danish twin population using genetic testing for zygosity are higher than previously reported using self-report. Although not statistically significant, the differences in monozygotic and dizygotic pairs indicate that genetic factors may be of importance for scoliosis. LEVEL OF EVIDENCE: 3.

Migraine with aura and risk of silent brain infarcts and white matter hyperintensities: an MRI study.

A small number of population-based studies reported an association between migraine with aura and risk of silent brain infarcts and white matter hyperintensities in females. We investigated these relations in a population-based sample of female twins. We contacted female twins ages 30-60 years identified through the population-based Danish Twin Registry. Based on questionnaire responses, twins were invited to participate in a telephone-based interview conducted by physicians. Headache diagnoses were established according to the International Headache Society criteria. Cases with migraine with aura, their co-twins, and unrelated migraine-free twins (controls) were invited to a brain magnetic resonance imaging scan performed at a single centre. Brain scans were assessed for the presence of infarcts, and white matter hyperintensities (visual rating scales and volumetric analyses) blinded to headache diagnoses. Comparisons were based on 172 cases, 34 co-twins, and 139 control subjects. Compared with control subjects, cases did not differ with regard to frequency of silent brain infarcts (four cases versus one control), periventricular white matter hyperintensity scores [adjusted mean difference (95% confidence interval): -0.1 (-0.5 to 0.2)] or deep white matter hyperintensity scores [adjusted mean difference (95% confidence interval): 0.1 (-0.8 to 1.1)] assessed by Scheltens' scale. Cases had a slightly higher total white matter hyperintensity volume compared with controls [adjusted mean difference (95% confidence interval): 0.17 (-0.08 to 0.41) cm(3)] and a similar difference was present in analyses restricted to twin pairs discordant for migraine with aura [adjusted mean difference 0.21 (-0.20 to 0.63)], but these differences did not reach statistical significance. We found no evidence of an association between silent brain infarcts, white matter hyperintensities, and migraine with aura.

A short leucocyte telomere length is associated with development of insulin resistance.

AIMS/HYPOTHESIS: A number of studies have shown that leucocyte telomere length (LTL) is inversely associated with insulin resistance and type 2 diabetes mellitus. The aim of the present longitudinal cohort study, utilising a twin design, was to assess whether shorter LTL predicts insulin resistance or is a consequence thereof. METHODS: Participants were recruited between 1997 and 2000 through the population-based national Danish Twin Registry to participate in the GEMINAKAR study, a longitudinal evaluation of metabolic disorders and cardiovascular risk factors. Baseline and follow-up measurements of LTL and insulin resistance over an average of 12 years were performed in a subset of the Registry consisting of 338 (184 monozygotic and 154 dizygotic) same-sex twin pairs. RESULTS: Age at baseline examination was 37.4 ± 9.6 (mean ± SD) years. Baseline insulin resistance was not associated with age-dependent changes in LTL (attrition) over the follow-up period, whereas baseline LTL was associated with changes in insulin resistance during this period. The shorter the LTL at baseline, the more pronounced was the increase in insulin resistance over the follow-up period (p < 0.001); this effect was additive to that of BMI. The co-twin with the shorter baseline LTL displayed higher insulin resistance at follow-up than the co-twin with the longer LTL. CONCLUSIONS/INTERPRETATION: These findings suggest that individuals with short LTL are more likely to develop insulin resistance later in life. By contrast, presence of insulin resistance does not accelerate LTL attrition.

A Danish Twin Study of Schizophrenia Liability: Investigation from Interviewed Twins for Genetic Links to Affective Psychoses and for Cross-Cohort Comparisons.

We studied schizophrenia liability in a Danish population-based sample of 44 twin pairs (13 MZ, 31 DZ, SS plus OS) in order to replicate previous twin study findings using contemporary diagnostic criteria, to examine genetic liability shared between schizophrenia and other disorders, and to explore whether variance in schizophrenia liability attributable to environmental factors may have decreased with successive cohorts exposed to improvements in public health. ICD-10 diagnoses were determined by clinical interview. Although the best-fitting, most parsimonious biometric model of schizophrenia liability specified variance attributable to additive genetic and non-shared environmental factors, this model did not differ significantly from a model that also included non-additive genetic factors, consistent with recent interview-based twin studies. Schizophrenia showed strong genetic links to other psychotic disorders but much less so for the broader category of psychiatric disorders in general. We also observed a marginally significant decline in schizophrenia variance attributable to environmental factors over successive Western European cohorts, consistent perhaps with improvements in diagnosis and in prenatal and perinatal care and with a secular decline in the prevalence of schizophrenia in that region.

Effect of Smoking on Blood Pressure and Resting Heart Rate: A Mendelian Randomization Meta-Analysis in the CARTA Consortium.

BACKGROUND: Smoking is an important cardiovascular disease risk factor, but the mechanisms linking smoking to blood pressure are poorly understood. METHODS AND RESULTS: Data on 141 317 participants (62 666 never, 40 669 former, 37 982 current smokers) from 23 population-based studies were included in observational and Mendelian randomization meta-analyses of the associations of smoking status and smoking heaviness with systolic and diastolic blood pressure, hypertension, and resting heart rate. For the Mendelian randomization analyses, a genetic variant rs16969968/rs1051730 was used as a proxy for smoking heaviness in current smokers. In observational analyses, current as compared with never smoking was associated with lower systolic blood pressure and diastolic blood pressure and lower hypertension risk, but with higher resting heart rate. In observational analyses among current smokers, 1 cigarette/day higher level of smoking heaviness was associated with higher (0.21 bpm; 95% confidence interval 0.19; 0.24) resting heart rate and slightly higher diastolic blood pressure (0.05 mm Hg; 95% confidence interval 0.02; 0.08) and systolic blood pressure (0.08 mm Hg; 95% confidence interval 0.03; 0.13). However, in Mendelian randomization analyses among current smokers, although each smoking increasing allele of rs16969968/rs1051730 was associated with higher resting heart rate (0.36 bpm/allele; 95% confidence interval 0.18; 0.54), there was no strong association with diastolic blood pressure, systolic blood pressure, or hypertension. This would suggest a 7 bpm higher heart rate in those who smoke 20 cigarettes/day. CONCLUSIONS: This Mendelian randomization meta-analysis supports a causal association of smoking heaviness with higher level of resting heart rate, but not with blood pressure. These findings suggest that part of the cardiovascular risk of smoking may operate through increasing resting heart rate.

Paternal age and telomere length in twins: the germ stem cell selection paradigm.

Telomere length, a highly heritable trait, is longer in offspring of older fathers. This perplexing feature has been attributed to the longer telomeres in sperm of older men and it might be an 'epigenetic' mechanism through which paternal age plays a role in telomere length regulation in humans. Based on two independent (discovery and replication) twin studies, comprising 889 twin pairs, we show an increase in the resemblance of leukocyte telomere length between dizygotic twins of older fathers, which is not seen in monozygotic twins. This phenomenon might result from a paternal age-dependent germ stem cell selection process, whereby the selected stem cells have longer telomeres, are more homogenous with respect to telomere length, and share resistance to aging.

The heritability of leucocyte telomere length dynamics.

BACKGROUND: Leucocyte telomere length (LTL) is a complex trait associated with ageing and longevity. LTL dynamics are defined by LTL and its age-dependent attrition. Strong, but indirect evidence suggests that LTL at birth and its attrition during childhood largely explains interindividual LTL variation among adults. A number of studies have estimated the heritability of LTL, but none has assessed the heritability of age-dependent LTL attrition. METHODS: We examined the heritability of LTL dynamics based on a longitudinal evaluation (an average follow-up of 12 years) in 355 monozygotic and 297 dizygotic same-sex twins (aged 19-64 years at baseline). RESULTS: Heritability of LTL at baseline was estimated at 64% (95% CI 39% to 83%) with 22% (95% CI 6% to 49%) of shared environmental effects. Heritability of age-dependent LTL attrition rate was estimated at 28% (95% CI 16% to 44%). Individually unique environmental factors, estimated at 72% (95% CI 56% to 84%) affected LTL attrition rate with no indication of shared environmental effects. CONCLUSIONS: This is the first study that estimated heritability of LTL and also its age-dependent attrition. As LTL attrition is much slower in adults than in children and given that having a long or a short LTL is largely determined before adulthood, our findings suggest that heritability and early life environment are the main determinants of LTL throughout the human life course. Thus, insights into factors that influence LTL at birth and its dynamics during childhood are crucial for understanding the role of telomere genetics in human ageing and longevity.