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The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural–geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.
Adverse health and social outcomes are known to occur more frequently following parental death during childhood, but evidence is lacking for comparing long-term risks of internalised v. externalised harm.
This national register-based cohort study consisted of Danish persons born 1970–2000. The Civil Registration System and National Causes of Death Register were linked to ascertain parental deaths by cause before cohort members' 15th birthdays. From age 15 years, hospital-treated self-harm episodes were ascertained through linkage to the National Patient Register and the Psychiatric Central Research Register, and violent crimes were identified via linkage to the National Crime Register. Hazard ratio and cumulative incidence values were estimated.
Self-harm and violent criminality risks were elevated following parental death during childhood. Covariate adjustment for gender, birth year and first-degree relatives' mental illnesses attenuated these associations, although significantly heightened risks persisted. The estimated hazard ratios did not differ greatly according to which parent died, but losing both parents conferred particularly large risk increases. Risks for both adverse outcomes were higher in relation to unnatural v. natural parental death; violent criminality risk was especially raised among individuals exposed to parental death by unnatural causes other than suicide. The association was strongest when pre-school age children experienced parental death.
Effective early intervention is needed to help youngsters who have experienced the death of one or both parents to develop immediate and sustained coping strategies. Enhanced cooperation between health and social services and criminal justice agencies may mitigate risks for these two destructive behaviours.
Piglet mortality in outdoor production systems varies across the year, and a reason for this variation could be fluctuations in hut climate, as ambient temperature might influence piglet survival, both directly and indirectly. Therefore, the aim of the current study was to investigate the impact of farrowing hut climate and year variation on stillbirth and liveborn mortality. A large-scale observational study was conducted at five commercial organic pig-producing herds in Denmark from June 2015 to August 2016. Both year variation (F3,635=4.40, P=0.004) and farrowing hut temperature (F2,511=6.46, P=0.002) affected the rate of stillbirths. The risk of stillborn piglets was lowest in winter and during this season larger changes in hut temperature between day 1 prepartum and the day of farrowing increased the risk of stillbirths (F1,99=6.39, P=0.013). In addition, during the warm part of the year stillbirth rate increased at temperatures ⩾27°C. Year variation also affected liveborn mortality (F3,561=3.86, P=0.009) with a lower rate of liveborn deaths in spring. However, the hut climate did not influence liveborn deaths. Consequently, other factors than hut climate may explain the influence of year variation on liveborn mortality. These could be light differences causing seasonality in reproduction and lactation.
Psychological treatment for functional somatic syndromes (FSS) has been found moderately effective. Information on how much treatment is needed to obtain improvement is sparse. We assessed the efficacy of a brief and extended version of group-based Acceptance and Commitment Therapy (ACT) v. enhanced care (EC) for patients with multiple FSS operationalised as Bodily Distress Syndrome multi-organ type.
In a randomised controlled three-armed trial, consecutively referred patients aged 20–50 with multiple FSS were randomly assigned to either (1) EC; (2) Brief ACT: EC plus 1-day workshop and one individual consultation; or (3) Extended ACT: EC plus nine 3-h group-based sessions. Primary outcome was patient-rated overall health improvement on the five-point clinical global improvement scale 14 months after randomisation. A proportional odds model was used for the analyses.
A total of 180 patients were randomised; 60 to EC, 61 to Brief ACT, and 59 to Extended ACT. Improvement on the primary outcome after Extended ACT was significantly greater than after EC with an unadjusted OR of 2.9 [95% CI (1.4–6.2), p = 0.006]. No significant differences were found between Brief ACT and EC. Of the 18 secondary outcomes, the only significant difference found was for physical functioning in the comparison of Extended ACT with EC.
Patients rated their overall health status as more improved after Extensive ACT than after EC; however, clinically relevant secondary outcome measures did not support this finding. Discrepancies between primary and secondary outcomes in this trial are discussed.
Whether monozygotic (MZ) and dizygotic (DZ) twins differ from each other in a variety of phenotypes is important for genetic twin modeling and for inferences made from twin studies in general. We analyzed whether there were differences in individual, maternal and paternal education between MZ and DZ twins in a large pooled dataset. Information was gathered on individual education for 218,362 adult twins from 27 twin cohorts (53% females; 39% MZ twins), and on maternal and paternal education for 147,315 and 143,056 twins respectively, from 28 twin cohorts (52% females; 38% MZ twins). Together, we had information on individual or parental education from 42 twin cohorts representing 19 countries. The original education classifications were transformed to education years and analyzed using linear regression models. Overall, MZ males had 0.26 (95% CI [0.21, 0.31]) years and MZ females 0.17 (95% CI [0.12, 0.21]) years longer education than DZ twins. The zygosity difference became smaller in more recent birth cohorts for both males and females. Parental education was somewhat longer for fathers of DZ twins in cohorts born in 1990–1999 (0.16 years, 95% CI [0.08, 0.25]) and 2000 or later (0.11 years, 95% CI [0.00, 0.22]), compared with fathers of MZ twins. The results show that the years of both individual and parental education are largely similar in MZ and DZ twins. We suggest that the socio-economic differences between MZ and DZ twins are so small that inferences based upon genetic modeling of twin data are not affected.
Maternal smoking has consistently been associated with multiple adverse childhood outcomes including externalizing disorders. In contrast the association between maternal smoking during pregnancy (MSDP) and internalizing (anxiety and depressive) disorders in offspring has received less investigation.
We conducted a nationwide cohort study including 957635 individuals born in Denmark between 1991 and 2007. Data on MSDP and diagnoses of depression or anxiety disorders were derived from national registers and patients were followed up from the age of 5 years to the end of 2012. Hazard rate ratios (HRRs) were estimated using stratified Cox regression models. Sibling data were used to disentangle individual- and familial-level effects of MSDP and to control for unmeasured familial confounding.
At the population level, offspring exposed to MSDP were at increased risk for both severe depression [HRR 1.29, 95% confidence interval (CI) 1.22–1.36] and severe anxiety disorders (HRR 1.26, 95% CI 1.20–1.32) even when controlling for maternal and paternal traits. However, there was no association between MSDP and internalizing disorders when controlling for the mother's propensity for MSDP (depression: HRR 1.11, 95% CI 0.94–1.30; anxiety disorders: HRR 0.94, 95% CI 0.80–1.11) or comparing differentially exposed siblings (depression: HRR 1.18, 95% CI 0.75–1.89; anxiety disorders: HRR 0.87, 95% CI 0.55–1.36).
The results suggest that familial background factors account for the association between MSDP and severe internalizing disorders not the specific exposure to MSDP.
Leptospirosis is the most widespread zoonosis in humans worldwide. In the United States, widespread detection of antibodies to leptospirosis have been identified in feral swine (Sus scrofa) with the highest detection of serovars, Bratislava, Icterohaemorrhagiae, and Pomona. Over the past few years, feral swine populations have expanded their geographical range and distribution in the United States with reports in at least 39 of 50 states. Since feral swine serve as reservoirs for serovars that can infect humans, it is important to understand the risk of transmission. In order to learn more about the probability that feral swine shed infectious leptospires, we collected kidneys and paired serum when possible from 677 feral swine in 124 counties of 29 states. These counties had previously been identified as antibody positive for Leptospira interrogans serovars Bratislava, Canicola, Grippotyphosa, Hardjo, Icterohaemorrhagiae or Pomona. Although exposure to these same six serovars of leptospirosis continued to be high (53% overall) in the counties we sampled, we detected leptospiral DNA in only 3·4% of feral swine kidneys tested. Based on these results, it appears that although feral swine can serve as a source of infection to humans, especially in those who are more likely to encounter them directly such as wildlife biologists, veterinarians, and hunters, the risk may be relatively low. However, further studies to examine the relationship between leptospiral shedding in the urine and kidneys in addition to culturing the organism are recommended in order to better understand the risk associated with feral swine.
A preoperative weight loss of 8 % is a prerequisite to undergo bariatric surgery (BS) in Denmark. The aim of the present study was to evaluate the efficacy of a 7- or an 11-week low-energy diet (LCD) for achieving preoperative target weight before BS. A total of thirty obese patients (BMI 46·0 (sd 4·4) kg/m2) followed an LCD (Cambridge Weight Plan®, 4184 kJ/d (1000 kcal/d)) for 7 or 11 weeks as preparation for BS. Anthropometric measurements including body composition (dual-energy X-ray absorptiometry), blood parameters and blood pressure were assessed at weeks 0, 7 and 11. At week 7, the majority of patients (77 %) had reached their target weight, and this was achieved after 5·4 (sem 0·3) weeks. Mean weight loss was 9·3 (sem 0·5) % (P < 0·01) and consisted of 41·6 % fat-free mass (FFM) and 58·4 % fat mass. The weight loss was accompanied by a decrease in systolic and diastolic blood pressure (7·1 (sem 2·3) and 7·3 (sem 1·8) mmHg, respectively, all P < 0·01) as well as an improved metabolic profile (8·2 (sem 1·8) % decrease in fasting glucose (P < 0·01), 28·6 (sem 6·4) % decrease in fasting insulin (P < 0·01), 23·1 (sem 2·2) % decrease in LDL (P < 0·01), and 9·7 (sem 4·7) % decrease in TAG (P < 0·05)). Weight, FFM and fat mass continued to decrease from week 7 to 11 (all P < 0·01), whereas no additional improvements was observed in the metabolic parameters. Severely obese patients can safely achieve preoperative target weight on an LCD within 7 weeks as part of preparation for BS. However, the considerable reduction in FFM in severely obese subjects needs further investigation.
Major depressive disorder (MDD) is moderately heritable, however genome-wide association studies (GWAS) for MDD, as well as for related continuous outcomes, have not shown consistent results. Attempts to elucidate the genetic basis of MDD may be hindered by heterogeneity in diagnosis. The Center for Epidemiological Studies Depression (CES-D) scale provides a widely used tool for measuring depressive symptoms clustered in four different domains which can be combined together into a total score but also can be analysed as separate symptom domains.
We performed a meta-analysis of GWAS of the CES-D symptom clusters. We recruited 12 cohorts with the 20- or 10-item CES-D scale (32 528 persons).
One single nucleotide polymorphism (SNP), rs713224, located near the brain-expressed melatonin receptor (MTNR1A) gene, was associated with the somatic complaints domain of depression symptoms, with borderline genome-wide significance (pdiscovery = 3.82 × 10−8). The SNP was analysed in an additional five cohorts comprising the replication sample (6813 persons). However, the association was not consistent among the replication sample (pdiscovery+replication = 1.10 × 10−6) with evidence of heterogeneity.
Despite the effort to harmonize the phenotypes across cohorts and participants, our study is still underpowered to detect consistent association for depression, even by means of symptom classification. On the contrary, the SNP-based heritability and co-heritability estimation results suggest that a very minor part of the variation could be captured by GWAS, explaining the reason of sparse findings.
We analyzed birth order differences in means and variances of height and body mass index (BMI) in monozygotic (MZ) and dizygotic (DZ) twins from infancy to old age. The data were derived from the international CODATwins database. The total number of height and BMI measures from 0.5 to 79.5 years of age was 397,466. As expected, first-born twins had greater birth weight than second-born twins. With respect to height, first-born twins were slightly taller than second-born twins in childhood. After adjusting the results for birth weight, the birth order differences decreased and were no longer statistically significant. First-born twins had greater BMI than the second-born twins over childhood and adolescence. After adjusting the results for birth weight, birth order was still associated with BMI until 12 years of age. No interaction effect between birth order and zygosity was found. Only limited evidence was found that birth order influenced variances of height or BMI. The results were similar among boys and girls and also in MZ and DZ twins. Overall, the differences in height and BMI between first- and second-born twins were modest even in early childhood, while adjustment for birth weight reduced the birth order differences but did not remove them for BMI.
Access to drinking water is essential for animal welfare, but it is unclear if temporary water restriction during the night represents a welfare problem. The aim of the present study was to investigate the effect of various durations of nightly restriction of water on thirst in loose housed lactating sows from day 10 to 28 of lactation. A total of 48 sows were deprived of water for either 0 h (n=12; control), 3 h (n=12; 0500 to 0800 h), 6 h (n=12; 0200 to 0800 h) or 12 h (n=12; 2000 to 0800 h). Control sows consumed 22% of their water intake during the night (2000 to 0800 h), whereas water consumption during this time was reduced to 13%, 7% and 0% in sows restricted for 3, 6 and 12 h. With increased duration of nightly water restriction a reduced latency to drink (26.8, 18.0, 5.3 and 6.7 min for 0, 3, 6 and 12 h sows; P<0.001) and an increased water intake during the 1st hour after water became accessible (2.1, 3.4, 4.7 and 5.6 l for 0, 3, 6 and 12 h sows; P<0.001) was seen. During the last 30 min before water became accessible more sows deprived of water investigated (0%, 50%, 75%,and 50% of 0, 3, 6 and 12 h sows; P<0.01) or forcefully manipulated (0%, 17%, 50% and 33% of 0, 3, 6 and 12 h sows; P<0.05) the water trough, suggesting frustration and a negative experience of thirst. When all signs of imminent water access were provided, but access was delayed by 25 min, a tendency for more of the sows deprived of water for 6 and 12 h to interact forcefully with the water trough was seen (22%, 18%, 42% and 67% of 0, 3, 6 and 12 h sows; P=0.09). Duration of water restriction did not affect water consumption on a 24-h basis, nursing behaviour or performance. In conclusion, behavioural indicators of thirst increased with increasing duration of nightly water restriction in lactating sows.
Twin pairs discordant for disease may help elucidate the epigenetic mechanisms and causal environmental factors in disease development and progression. To obtain the numbers of pairs, especially monozygotic (MZ) twin pairs, necessary for in-depth studies while also allowing for replication, twin studies worldwide need to pool their resources. The Discordant Twin (DISCOTWIN) consortium was established for this goal. Here, we describe the DISCOTWIN Consortium and present an analysis of type 2 diabetes (T2D) data in nearly 35,000 twin pairs. Seven twin cohorts from Europe (Denmark, Finland, Norway, the Netherlands, Spain, Sweden, and the United Kingdom) and one from Australia investigated the rate of discordance for T2D in same-sex twin pairs aged 45 years and older. Data were available for 34,166 same-sex twin pairs, of which 13,970 were MZ, with T2D diagnosis based on self-reported diagnosis and medication use, fasting glucose and insulin measures, or medical records. The prevalence of T2D ranged from 2.6% to 12.3% across the cohorts depending on age, body mass index (BMI), and national diabetes prevalence. T2D discordance rate was lower for MZ (5.1%, range 2.9–11.2%) than for same-sex dizygotic (DZ) (8.0%, range 4.9–13.5%) pairs. Across DISCOTWIN, 720 discordant MZ pairs were identified. Except for the oldest of the Danish cohorts (mean age 79), heritability estimates based on contingency tables were moderate to high (0.47–0.77). From a meta-analysis of all data, the heritability was estimated at 72% (95% confidence interval 61–78%). This study demonstrated high T2D prevalence and high heritability for T2D liability across twin cohorts. Therefore, the number of discordant MZ pairs for T2D is limited. By combining national resources, the DISCOTWIN Consortium maximizes the number of discordant MZ pairs needed for in-depth genotyping, multi-omics, and phenotyping studies, which may provide unique insights into the pathways linking genes to the development of many diseases.
A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m2 in childhood and adolescence and up to 0.2 kg/m2 in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes.
The gut microbiota has been implicated in obesity and its progression towards metabolic disease. Dietary interventions that target the gut microbiota have been suggested to improve metabolic health. The aim of the present study was to investigate the effect of interventions with Lactobacillus paracasei F19 or flaxseed mucilage on the gut microbiota and metabolic risk markers in obesity. A total of fifty-eight obese postmenopausal women were randomised to a single-blinded, parallel-group intervention of 6-week duration, with a daily intake of either L. paracasei F19 (9·4 × 1010 colony-forming units), flaxseed mucilage (10 g) or placebo. Quantitative metagenomic analysis of faecal DNA was performed to identify the changes in the gut microbiota. Diet-induced changes in metabolic markers were explored using adjusted linear regression models. The intake of flaxseed mucilage over 6 weeks led to a reduction in serum C-peptide and insulin release during an oral glucose tolerance test (P< 0·05) and improved insulin sensitivity measured by Matsuda index (P< 0·05). Comparison of gut microbiota composition at baseline and after 6 weeks of intervention with flaxseed mucilage showed alterations in abundance of thirty-three metagenomic species (P< 0·01), including decreased relative abundance of eight Faecalibacterium species. These changes in the microbiota could not explain the effect of flaxseed mucilage on insulin sensitivity. The intake of L. paracasei F19 did not modulate metabolic markers compared with placebo. In conclusion, flaxseed mucilage improves insulin sensitivity and alters the gut microbiota; however, the improvement in insulin sensitivity was not mediated by the observed changes in relative abundance of bacterial species.
The effects of early life events on average daily weight gain from birth to day 21 (ADG) of suckling pigs kept at different room temperatures (15°C, 20°C and 25°C) from birth to weaning were investigated. Data were collected from litters born by 61 sows in a loose housing system. The ADG for piglets with low birth weight (estimated for birth weights below the 10% percentile) was estimated to be 20 to 30 g higher per day at room temperature 20°C to 25°C compared with 15°C. In contrast, the ADG during the lactation period decreased for larger piglets (estimated for birth weights above the 10% percentile) by 28 g/day at room temperature 25°C compared with 15°C. Thus, high ambient temperatures (20°C to 25°C) are favourable for the growth in smaller piglets during lactation. Neither latency to first suckle nor birth-induced hypoxia, measured as concentration of umbilical cord lactate, affected the growth rate of the piglets. Lowest rectal temperature during the first 24 h after birth had a long-term negative effect on ADG (P<0.05), so that piglets with a lowest rectal temperature of 32.8°C (10% percentile) had an ADG which was on average 19 g lower per day than piglets with a rectal temperature of 37.3°C (90% percentile). Our results showed that hypothermia at birth, low birth weight and high number of suckling piglets lead to reduced ADG during the suckling period. The results suggest that keeping the room temperature at 20°C during lactation to some extent could compensate for the otherwise negative effects of low birth weight on ADG in piglets without decreasing the ADG of high birth weight piglets. However, to avoid hypothermia in the smallest piglets it may be beneficial to increase the room temperature above 20°C during the farrowing period of loose housed sows.
For over 100 years, the genetics of human anthropometric traits has attracted scientific interest. In particular, height and body mass index (BMI, calculated as kg/m2) have been under intensive genetic research. However, it is still largely unknown whether and how heritability estimates vary between human populations. Opportunities to address this question have increased recently because of the establishment of many new twin cohorts and the increasing accumulation of data in established twin cohorts. We started a new research project to analyze systematically (1) the variation of heritability estimates of height, BMI and their trajectories over the life course between birth cohorts, ethnicities and countries, and (2) to study the effects of birth-related factors, education and smoking on these anthropometric traits and whether these effects vary between twin cohorts. We identified 67 twin projects, including both monozygotic (MZ) and dizygotic (DZ) twins, using various sources. We asked for individual level data on height and weight including repeated measurements, birth related traits, background variables, education and smoking. By the end of 2014, 48 projects participated. Together, we have 893,458 height and weight measures (52% females) from 434,723 twin individuals, including 201,192 complete twin pairs (40% monozygotic, 40% same-sex dizygotic and 20% opposite-sex dizygotic) representing 22 countries. This project demonstrates that large-scale international twin studies are feasible and can promote the use of existing data for novel research purposes.
As feral swine continue to expand their geographical range and distribution across the United States, their involvement in crop damage, livestock predation, and pathogen transmission is likely to increase. Despite the relatively recent discovery of feral swine involvement in the aetiology of a variety of pathogens, their propensity to transmit and carry a wide variety of pathogens is disconcerting. We examined sera from 2055 feral swine for antibody presence to six serovars of Leptospira that can also infect humans, livestock or domestic animals. About 13% of all samples tested positive for at least one serovar, suggesting that Leptospira infection is common in feral swine. Further studies to identify the proportion of actively infected animals are needed to more fully understand the risk they pose.