[Show abstract][Hide abstract] ABSTRACT: Copy number variants (CNVs) represent a significant source of genetic variation in the human genome and have been implicated in numerous diseases and complex traits. To date, only a few studies have investigated the role of CNVs in human lifespan. To investigate the impact of CNVs on prospective mortality at the extreme end of life, where the genetic component of lifespan appears most profound, we analyzed genomewide CNV data in 603 Danish nonagenarians and centenarians (mean age 96.9 years, range 90.0-102.5 years). Replication was performed in 500 long-lived individuals from the Leiden Longevity Study (mean age 93.2 years, range 88.9-103.4 years). First, we assessed the association between the CNV burden of each individual (the number of CNVs, the average CNV length, and the total CNV length) and mortality and found a significant increase in mortality per 10 kb increase in the average CNV length, both for all CNVs (hazard ratio (HR) = 1.024, P = 0.002) and for duplications (HR = 1.011, P = 0.005), as well as per 100 kb increase in the total length of deletions (HR = 1.009, P = 0.0005). Next, we assessed the relation between specific deletions and duplications and mortality. Although no genome-wide significant associations were discovered, we identified six deletions and one duplication that showed consistent association with mortality in both or either of the sexes across both study populations. These results indicate that the genome-wide CNV burden, specifically the average CNV length and the total CNV length, associates with higher mortality in long-lived individuals.
[Show abstract][Hide abstract] ABSTRACT: Decline in cognitive abilities is a major concern in aging individuals. A potential important factor for functioning of the central nervous system in late-life stages is the KLOTHO (KL) gene. KL is expressed in various organs including the brain and is involved in multiple biological processes, for example, growth factor signaling. In the present study, 19 tagging gene variants in KL were studied in relation to 2 measures of cognitive function, a 5-item cognitive composite score and the Mini Mental State Examination, in 1,480 Danes 92-100 years of age. We found that heterozygotes for the previously reported KL-VS had poorer cognitive function than noncarriers. Two other variants positioned in the 5' end of the gene, rs398655 and rs562020, were associated with better cognitive function independently of KL-VS, and the common haplotype AG was associated with poorer cognition, consistently across two cognitive measures in two cohort strata. The haplotype effect was stronger than that of KL-VS. Two variants, rs2283368 and rs9526984, were the only variants significantly associated with cognitive decline over 7 years. We discuss an age-dependent effect of KL and the possibility that multiple gene variants in KL are important for cognitive function among the oldest old participants.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 09/2015; DOI:10.1093/gerona/glv163 · 5.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: A longer leukocyte telomere length (LTL) in women than men has been attributed to a slow rate of LTL attrition in women, perhaps due to high estrogen exposure during the premenopausal period.
Methods: To test this premise we performed a longitudinal study (an average follow-up of 12 years) in subset of the population-based Danish National Twin Registry. Participants consisted of 405 women, aged 37.5 (range 18.0 - 64.3) years, and 329 men, aged 38.8 (range 18.0 - 58.5) years, at baseline examination.
Results: Women showed a longer LTL (kb ± SE) than men (baseline: 7.01 ± 0.03 vs. 6.87 ± 0.04; follow-up: 6.79 ± 0.03 vs. 6.65 ± 0.03; both p=0.005). Women displayed deceleration of LTL attrition (bp/years ± SE), as they transitioned from the premenopausal period (20.6 ± 1.0) through the perimenopausal period (16.5 ± 1.3) to the postmenopausal period (15.1 ± 1.7). Age was not associated with LTL attrition in women after statistical control for menopausal status. Men, in contrast, displayed a trend for age-dependent increase in the rate of LTL attrition, which differed significantly from the pattern in women (p for interaction=0.01).
Conclusions: Results indicate that the premenopausal period is expressed in a higher rate of LTL attrition than the postmenopausal period. They further suggest that the sex gap in LTL stems from earlier ages─ the period of growth and development. The higher rate of LTL attrition in premenopausal women, we propose, might relate to estrogen-mediated increased turnover of erythrocytes, menstrual bleeding or both.
International Journal of Epidemiology 09/2015; on line. DOI:10.1093/ije/dyv165 · 9.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Epidemiological studies have reported that a higher perceived age is associated with poor health and higher mortality. However, the method used for the assessment of perceived age differs between studies with regard to age, gender, the number and occupation of assessors as well as the presentation of participants.
It is not known whether the clinical experience of the assessor or photographic presentation have an influence on the assessment of perceived age, which the present study aimed to investigate.
In a cross-sectional study of 460 women aged 25-93 years, 10 consultants and 10 residents were asked to estimate the age of each participant using three different photographic presentations: facial photograph, whole-body photograph, and combined facial and whole-body photographs. Data were analyzed by means of summary statistics and linear mixed models.
The inter-class correlation coefficient within each assessor group and photographic presentation varied from 0.66 to 0.75. Limits of agreement were in a broad range but were similar in the two assessor groups. The best inter-assessor agreement was obtained from photographs of both the face and the whole body. Intra- and inter-assessor agreements between photographic presentations were similar among both assessor groups. The accuracy in age assessment was significantly influenced by the photographic presentation but not by the clinical experience of the assessor. The difference in the mean perceived age of a participant of average age was estimated as +0.40 years (95% CI: -1.80; 2.59) for consultants versus residents, -2.05 years (95% CI: -2.90; -1.19) for facial photographs versus both facial and whole-body photographs, and -1.44 years (95% CI: -2.30; -0.58) for whole-body photographs versus both facial and whole-body photographs. A regression towards the mean age was seen.
The assessment of perceived age was influenced by the photographic presentation but not by the clinical experience of the assessor.
[Show abstract][Hide abstract] ABSTRACT: Van der Woude syndrome (VWS) is an autosomal dominant malformation syndrome characterized by orofacial clefting (OFC) and lower lip pits. The clinical presentation of VWS is variable and can present as an isolated OFC, making it difficult to distinguish VWS cases from individuals with nonsyndromic OFCs. About 70% of causal VWS mutations occur in IRF6, a gene that is also associated with nonsyndromic OFCs. Screening for IRF6 mutations in apparently nonsyndromic cases has been performed in several modestly sized cohorts with mixed results. In the current study we screened 1521 trios with presumed nonsyndromic OFCs to determine the frequency of causal IRF6 mutations. We identified seven likely causal IRF6 mutations, although a posteriori review identified two misdiagnosed VWS families based on the presence of lip pits. We found no evidence for association between rare IRF6 polymorphisms and nonsyndromic OFCs. We combined our results with other similar studies (totaling 2,472 families) and conclude that causal IRF6 mutations are found in 0.24%-0.44% of apparently nonsyndromic OFC families. We suggest that clinical mutation screening for IRF6 be considered for certain family patterns such as families with mixed types of OFCs and/or autosomal dominant transmission.
[Show abstract][Hide abstract] ABSTRACT: 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/m
in childhood and adolescence and up to 0.2 kg/m
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.
Twin Research and Human Genetics 09/2015; DOI:10.1017/thg.2015.57 · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Age-related decline in grip strength predicts later life disability, frailty, lower well-being and cognitive change. While grip strength is heritable, genetic influence on change in grip strength has been relatively ignored, with non-shared environmental influence identified as the primary contributor in a single longitudinal study. The extent to which gene-environment interplay, particularly gene-environment interactions, contributes to grip trajectories has yet to be examined. We considered longitudinal grip strength measurements in seven twin studies of aging in the Interplay of Genes and Environment across Multiple Studies consortium. Growth curve parameters were estimated for same-sex pairs, aged 34-99 (N = 10,681). Fisher's test for mixture distribution of within-monozygotic twin-pair differences (N = 1724) was performed on growth curve parameters. We observed significant gene-environment interaction on grip strength trajectories. Finally, we compared the variability of within-pair differences of growth curve parameters by APOE haplotypes. Though not statistically significant, the results suggested that APOE ɛ2ɛ2/ɛ2ɛ3 haplotypes might buffer environmental influences on grip strength trajectories.
[Show abstract][Hide abstract] ABSTRACT: To investigate whether depression symptomatology is associated with low back pain (LBP) in twins aged 70+ and whether this effect depends on a person's physical activity (PA) status.
This prospective cohort and nested case-control study used a nationally representative sample of twins. Data on depression symptomatology (modified Cambridge Mental Disorders Examination) and self-reported PA were obtained from the Longitudinal Study of Aging Danish Twins using twins without LBP at baseline. Associations between depression symptomatology (highest quartile) at baseline and LBP two years later were investigated using logistic regression analyses adjusted for sex. To examine the moderating effect of PA, we tested its interaction with depression. Associations were analysed using the complete sample of 2446 twins and a matched case-control analysis of 97 twin pairs discordant for LBP at follow-up. Odds ratios (OR) with 95 % confidence intervals (CI) were calculated.
Using the whole sample, high depression scores were associated with an increased probability of LBP (OR 1.56, 95 % CI 1.22-1.99, P ≤ 0.01). There was no statistically significant interaction of light PA and depression symptomatology (OR 0.78, 95 % CI 0.46-1.35, P = 0.39) and strenuous PA and depression symptomatology (0.84, 95 % CI 0.50-1.41, P = 0.51). The case-control analysis showed similar ORs, although statistically insignificant.
High depression symptomatology predicted incident LBP. This effect is supposedly not attributable to genetic or shared environmental factors. Physical activity did not moderate the effect of depression symptomatology on LBP.
European Spine Journal 08/2015; DOI:10.1007/s00586-015-4138-0 · 2.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Several studies in the new field of cognitive epidemiology have shown that higher intelligence predicts longer lifespan. This positive correlation might arise from socioeconomic status influencing both intelligence and health; intelligence leading to better health behaviours; and/or some shared genetic factors influencing both intelligence and health. Distinguishing among these hypotheses is crucial for medicine and public health, but can only be accomplished by studying a genetically informative sample.
We analysed data from three genetically informative samples containing information on intelligence and mortality: Sample 1, 377 pairs of male veterans from the NAS-NRC US World War II Twin Registry; Sample 2, 246 pairs of twins from the Swedish Twin Registry; and Sample 3, 784 pairs of twins from the Danish Twin Registry. The age at which intelligence was measured differed between the samples. We used three methods of genetic analysis to examine the relationship between intelligence and lifespan: we calculated the proportion of the more intelligent twins who outlived their co-twin; we regressed within-twin-pair lifespan differences on within-twin-pair intelligence differences; and we used the resulting regression coefficients to model the additive genetic covariance. We conducted a meta-analysis of the regression coefficients across the three samples.
The combined (and all three individual samples) showed a small positive phenotypic correlation between intelligence and lifespan. In the combined sample observed r = .12 (95% confidence interval .06 to .18). The additive genetic covariance model supported a genetic relationship between intelligence and lifespan. In the combined sample the genetic contribution to the covariance was 95%; in the US study, 84%; in the Swedish study, 86%, and in the Danish study, 85%.
The finding of common genetic effects between lifespan and intelligence has important implications for public health, and for those interested in the genetics of intelligence, lifespan or inequalities in health outcomes including lifespan.
International Journal of Epidemiology 07/2015; DOI:10.1093/ije/dyv112 · 9.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The apparent contradiction that women live longer but have worse health than men, the so called male-female health-survival paradox, is very pronounced in Russia. The present study investigates whether men in Moscow are healthier than women at the level of biomarkers, and whether the associations between biomarkers and subjective health have sex-specific patterns.
Previously collected data in the study of Stress, Aging, and Health in Russia (SAHR, n = 1800) were used to examine sex differences in biomarkers and their associations with physical functioning and self-rated health.
The present study found mixed directions and magnitudes for sex differences in biomarkers. Women were significantly disadvantaged with regard to obesity and waist circumference, whereas men had a tendency toward higher prevalence of electrocardiographic abnormalities. No sex differences were indicated in the prevalence of immunological biomarkers, and mixed patterns were found for lipid profiles. Many biomarkers were associated with physical functioning and general health. Obesity and waist circumference were related to lower physical functioning among females only, while major Q-wave abnormalities with high probabilities of myocardial infarction and atrial fibrillation or atrial flutter were associated with physical functioning and self-rated health among males only.
No clear patterns of sex differences in prevalence of high-risk levels of biomarkers suggest that the male-female health-survival paradox is weaker at the level of health biomarkers. We found some evidence that certain biomarkers reflecting pathophysiological changes in the organism that do not possess acute health risks, but over many years may lead to physical disability, are associated with physical functioning and self-rated health in women, whereas others reflecting more serious life-threatening pathophysiological changes are associated with physical functioning and self-rated health in men.
PLoS ONE 06/2015; 10(6):e0131691. DOI:10.1371/journal.pone.0131691 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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/m
) 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.
Twin Research and Human Genetics 05/2015; 10(10):1017. DOI:10.1017/thg.2015.29 · 2.30 Impact Factor