Rare Genetic Variants Correlate with Better Processing Speed

We conducted a genome-wide association study (GWAS) of Digit Symbol Substitution Test (DSST) scores administered in 4207 family members of the Long Life Family Study (LLFS). Genotype data were imputed to the HRC panel of 64,940 haplotypes resulting in ~15M genetic variants with quality score > 0.7. The results were replicated using genetic data imputed to the 1000 Genomes phase 3 reference panel from two Danish twin cohorts: the study of Middle Aged Danish Twins and the Longitudinal Study of Aging Danish Twins. The GWAS in LLFS discovered 20 rare genetic variants (minor allele frequency (MAF) < 1.0%) that reached genome-wide significance (p-value < 5x10-8). Among these, 18 variants had large protective effects on the processing speed, including rs7623455, rs9821776, rs9821587, rs78704059 on chromosome 3, which were replicated in the combined Danish twin cohort. These SNPs are located in/near two genes, THRB and RARB, that belonged to thyroid hormone receptors family that may influence speed of metabolism and cognitive aging. The gene-level tests in LLFS confirmed that these two genes are associated with processing speed.

Toll-like receptor 4 methylation grade is linked to depressive symptom severity

This study explores potential associations between the methylation of promoter-associated CpG sites of the toll-like receptor (TLR)-family, plasma levels of pro-inflammatory proteins and depressive symptoms in young female psychiatric patients. Ratings of depressive symptoms and blood samples were obtained from 92 young women seeking psychiatric care. Methylation of 32 promoter-associated CpG sites in TLR1 to TLR10 was analysed using the Illumina Infinium Methylation EPIC BeadChip. Expression levels of 91 inflammatory proteins were determined by proximity extension assay. Statistical correlations between depressive state, TLR1-10 methylation and inflammatory proteins were investigated. Four additional cohorts were studied to evaluate the generalizability of the findings. In the discovery cohort, methylation grade of cg05429895 (TLR4) in blood was inversely correlated with depressive symptoms score in young adults. After correction for multiple testing, plasma levels of macrophage inflammatory protein 1β (MIP-1β/CCL4) were associated with both TLR4 methylation and depressive symptom severity. A similar inverse association between TLR4 methylation in blood and affective symptoms score was also found in a cohort of 148 both males and females (<40 years of age) from the Danish Twin Registry. These findings were not, however, replicated in three other external cohorts; which differed from the first two cohorts by a higher age and mixed ethnicities, thus limiting the generalizability of our findings. However, TLR4 methylation inversely correlated with TLR4 mRNA expression in the Danish Twin Study indicating a functional significance of methylation at this particular CpG. Higher depression scores in young Scandinavian adults was associated with decreased methylation of TLR4 in blood.

Increased serum SP-D in identification of high-risk smokers at high risk of COPD

Pulmonary surfactant protein D (SP-D) is an important component of the pulmonary innate immune system with the ability to dampen cigarette smoke-induced lung inflammation. However, cigarette smoking mediates translocation of SP-D from the lung to the blood, and serum SP-D (sSP-D) has therefore previously been suggested as marker for smoke-induced lung injury. In support of this notion, associations between high sSP-D and low lung function measurements have previously been demonstrated in smokers and in COPD. The present investigations employ a 12-year longitudinal Danish twin study to test the hypothesis that baseline sSP-D variation has the capacity to identify smokers with normal baseline lung function who are in high risk of significant future smoke-induced lung function decline. We find that sSP-D is significantly increased in those with normal lung function at baseline that develop lung function decline during follow up compared to those who stay lung healthy. Moreover, we demonstrate that it is the smoke-induced baseline sSP-D level, and not the constitutional level, which has capacity as biomarker, and which is linearly increased with the decline in lung function during follow up. In conclusion, we here present first observation of increased sSP-D for identification of high-risk smokers.

The Danish Twin Registry: An Updated Overview

The Danish Twin Registry (DTR) was established in the 1950s, when twins born from 1870 to 1910 were ascertained, and has since been extended to include twins from birth cohorts until 2009. The DTR currently comprises of more than 175,000 twins from the 140 birth cohorts. This makes the DTR the oldest nationwide twin register and among the largest in the world. The combination of data from several surveys, including biological samples and repeated measurements on the same individuals, and data from Danish national registers provides a unique resource for a wide range of twin studies. This article provides an updated overview of the data in the DTR: First, we provide a summary of the establishment of the register, the different ascertainment methods and the twins included; then follows an overview of major surveys conducted in the DTR since 1994 and a description of the DTR biobank, including a description of the molecular data created so far; finally, a short description is given of the linkage to Danish national registers at Statistics Denmark and some recent examples of studies using the various data resources in the DTR are highlighted.

The risk of asthma is increased among women with polycystic ovary syndrome: a twin study

BackgroundRecent registry studies have demonstrated a higher prevalence of asthma among women with polycystic ovary syndrome (PCOS). We aimed to assess the association and heritability of PCOS and asthma in a Danish twin cohort.MethodsData for 32 382 female twins from the Danish Twin Registry were included. Twins with PCOS were identified by searching the Danish National Patient Registry for International Classification of Diseases-10 code E28.2. Asthma was diagnosed by questionnaires.Results103 (0.3%) women had a PCOS diagnosis. The risk of asthma was increased among women with PCOS compared with women without (18% versus 9%, respectively; OR 2.11 (95% CI 1.13–3.96); p=0.02). After adjustment for age, body mass index, alcohol consumption and smoking status, the risk of asthma was still increased, but was no longer statistically significant (OR 1.54 (95% CI 0.75–3.17); p=0.24). Variance components analysis showed that shared environmental factors explained 49% (95% CI 24–68%) and unique environmental factors explained 51% (95% CI 32–76%) of the susceptibility to PCOS. For asthma, 44% (95% CI 28–61%) of the variance was explained by genetic factors, whereas 25% (95% CI 11–38%) was ascribable to shared environmental factors and 31% (95% CI 26–36%) to unique environmental factors.ConclusionThe risk of asthma is twice as high among female twins with PCOS. The individual susceptibility to PCOS is mainly due to environmental factors and not genetics.

Lifespans of Twins: Does Zygosity Matter?

Studies with twins provide fundamental insights to lifespans of humans. We aim to clarify if monozygotic and dizygotic twin individuals differ in lifespan, that is, if zygosity matters. We investigate whether a possible difference in mortality after infancy between zygosities is stable in different age cohorts, and whether the difference remains when twins with unknown zygosity are taken into account. Further, we compare the distribution of long-livers, that is, the upper-tail of the lifespan distribution, between monozygotic and same-sex dizygotic twin individuals. The Danish Twin Registry provides a nationwide cohort of 109,303 twins born during 1870 to 1990 with valid vital status. Standard survival analysis is used to compare mortality in monozygotic and dizygotic twin individuals and twin individuals with unknown zygosity. The mortality of monozygotic and dizygotic twin individuals differs slightly after taking into consideration effects of birth- and age-cohorts, gender differences, and that twins are paired. However, no substantial nor systematic differences remain when taking twins with unknown zygosity into account. Further, the distribution of long-livers is very similar by zygosity, suggesting the same mortality process. The population-based and oldest twin cohort ever studied suggests that monozygotic and dizygotic twins have similar lifespans.

Myeloproliferative Neoplasms in Danish Twins

Objective: Myeloproliferative neoplasms (MPNs) are a heterogeneous group of diseases characterized by clonal hyperproliferation of immature and mature cells of the myeloid lineage. Genetic differences have been proposed to play a role in the development of MPNs. Monozygotic twin pairs with MPNs have been reported in a few case reports, but the MPN concordance pattern in twins remains unknown. Method: All twin pairs born in the period 1900–2010 were identified in the nationwide Danish Twin Registry. Only pairs with both twins alive on January 1, 1977, and those born thereafter were included to allow identification in the Danish National Patient Registry. Results: A total of 158 twin pairs were registered with an MPN diagnosis: 36 monozygotic, 104 dizygotic, and 18 pairs with unknown zygosity. MPNs were diagnosed in both twins in 4 pairs. The probandwise concordance rates for monozygotic twin pairs were higher than for dizygotic twin pairs (15 vs. 0%; p = 0.016). Conclusion: An estimated concordance rate of 15% (95% CI 0.059–0.31) is modest, but given the rarity of MPNs this finding is clinically relevant and provides further support for the role of genetic predisposition in the development of MPNs.

Heritability of resting heart rate and association with mortality in middle-aged and elderly twins

ObjectiveResting heart rate (RHR) possibly has a hereditary component and is associated with longevity. We used the classical biometric twin study design to investigate the heritability of RHR in a population of middle-aged and elderly twins and, furthermore, studied the association between RHR and mortality.MethodsIn total, 4282 twins without cardiovascular disease were included from the Danish Twin Registry, hereof 1233 twin pairs and 1816 ‘single twins’ (twins with a non-participating co-twin); mean age 61.7 (SD 11.1) years; 1334 (31.2%) twins died during median 16.3 (IQR 13.8–16.5) years of follow-up assessed through Danish national registers. RHR was assessed by palpating radial pulse.ResultsWithin pair correlations for RHR adjusted for sex and age were 0.23 (95% CI 0.14 to 0.32) and 0.10 (0.03 to 0.17) for RHR in monozygotic (MZ) and dizygotic (DZ) twin pairs, respectively. Overall, heritability estimates were 0.23 (95% CI 0.15 to 0.30); 0.27 (0.15 to 0.38) for males and 0.17 (0.06 to 0.28) for females. In multivariable models adjusting for age, gender, body mass index, diabetes, hypertension, pulmonary function, smoking, physical activity and zygosity, RHR was significantly associated with mortality (eg, RHR >90 vs 61–70 beats per min: all-cause HR 1.56 (95% CI 1.21 to 2.03); cardiovascular 2.19 (1.30 to 3.67). Intrapair twin comparison revealed that the twin with the higher RHR was significantly more likely to die first and the probability increased with increase in intrapair difference in RHR.ConclusionsRHR is a trait with a genetic influence in middle-aged and elderly twins free of cardiovascular disease. RHR is independently associated with longevity even when familial factors are controlled for in a twin design.