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Aging is often associated with an increasing number of comorbidities that warrant use of multiple drugs which increases the use of potentially inappropriate medications (PIMs), drug–drug interactions (DDIs) and drug‐related problems (DRPs). The aim is to assess the prevalence of polypharmacy, PIMs, DDIs and DRPs among Faroese residents aged ≥90 years. In this population‐based cross‐sectional study, 494 individuals ≥90 years were invited and 298 (60%) participated. A pharmacist‐led medication review was performed based on self‐information, electronic patient journal and the Faroese Prescription Registry. The prevalence of polypharmacy was 74% with no sex‐difference. Approximately 60% of participants used PIMs, primarily benzodiazepines and proton pump inhibitors, the latter being a frequently implicated medication in DRPs. Opioid use was low compared with other Nordic studies. DRPs were observed for 79% with discrepancies in the medication lists as the most common cause, and DDIs were identified for 47% of participants, mostly moderately clinically relevant DDIs. In conclusion, the medication use among the oldest old Faroese resembled that in other Nordic countries with a high prevalence of polypharmacy and use of PIMs, especially PPIs and benzodiazepines. However, no sex‐difference was noted in medication use and the use of opioids was low. [ABSTRACT FROM AUTHOR]

Background: Higher levels of frailty, quantified by a frailty index (FI), may be linked to fatigue severity as tasks become more physically and mentally demanding. Fatigue, a component of frailty research, has been ambiguous and inconsistent in its operationalization. Fatigability—the quantification of vulnerability to fatigue in relation to specific intensity and duration of activities—offers a more sensitive and standardized approach, though the association between frailty and fatigability has not been assessed. Methods: Using cross‐sectional data from the Long Life Family Study at Visit 2 (2014–2017; N = 2524; mean age ± standard deviation (SD) 71.4 ± 11.2 years; 55% women; 99% White), we examined associations between an 83‐item FI after excluding fatigue items (ratio of number of health problems reported (numerator) out of the total assessed (denominator); higher ratio = greater frailty) and perceived physical and mental fatigability using the Pittsburgh Fatigability Scale (PFS) (range 0–50; higher scores = greater fatigability). Results: Participants had mean ± standard deviation FI (0.08 ± 0.06; observed range: 0.0–0.43), PFS Physical (13.7 ± 9.6; 39.5% more severe, ≥15), and PFS Mental (7.9 ± 8.9; 22.8% more severe, ≥13). The prevalence of more severe physical and mental fatigability was higher across FI quartiles. In mixed effects models accounting for family structure, a clinically meaningful 3%‐higher FI was associated with 1.9 points higher PFS Physical score (95% confidence interval (CI) 1.7–2.1) and 1.7 points higher PFS Mental score (95% CI 1.5–1.9) after adjusting for covariates. Conclusions: Frailty was associated with perceived physical and mental fatigability severity. Understanding this association may support the development of interventions to mitigate the risks associated with greater frailty and perceived fatigability. Including measurements of perceived fatigability, in lieu of fatigue, in frailty indices has the potential to alleviate the inconsistencies and ambiguity surrounding the operationalization of fatigue and provide a more precise and sensitive measurement of frailty. [ABSTRACT FROM AUTHOR]

Despite the proliferation of research on public service motivation (PSM), fundamental questions about its origins continue to evade scholars: Is PSM driven by genetics, socialized through experiences, or both? If PSM is socialized, when does socialization occur? Answering these questions is critical for reconciling the state versus trait debate, and for assessing the validity of practical implications prescribed by PSM studies. Utilizing "nature's own experiment," we adopt a classical twin design with 1035 twin pairs to identify how genetic heritability, a common environment, or unique environment and experiences can explain variation in PSM. Results show that PSM is heavily influenced by individuals' unique environments and experiences; not by genetics. This lends strong evidence to PSM's uniqueness as a motivational construct as related "other‐regarding" concepts show sizeable genetic components. Finally, our results corroborate that PSM is a human resource with dynamic properties organizations can cultivate to enhance productivity in public service workforces. [ABSTRACT FROM AUTHOR]

Age‐related diseases characteristic of post‐reproductive life, aging, and life span are the examples of polygenic non‐Mendelian traits with intricate genetic architectures. Polygenicity of these traits implies that multiple variants can impact their risks independently or jointly as combinations of specific variants. Here, we examined chances to live to older ages, 85 years and older, for carriers of compound genotypes comprised of combinations of genotypes of rs429358 (APOE ɛ4 encoding polymorphism), rs2075650 (TOMM40), and rs12721046 (APOC1) polymorphisms using data from four human studies. The choice of these polymorphisms was motivated by our prior results showing that the ɛ4 carriers having minor alleles of the other two polymorphisms were at exceptionally high risk of Alzheimer's disease (AD), compared with non‐carriers of the minor alleles. Consistent with our prior findings for AD, we show here that the adverse effect of the ɛ4 allele on survival to older ages is significantly higher in carriers of minor alleles of rs2075650 and/or rs12721046 polymorphisms compared with their non‐carriers. The exclusion of AD cases made this effect stronger. Our results provide compelling evidence that AD does not mediate the associations of the same compound genotypes with chances to survive until older ages, indicating the existence of genetically heterogeneous mechanisms. The survival chances can be mainly associated with lipid‐ and immunity‐related mechanisms, whereas the AD risk, can be driven by the AD‐biomarker‐related mechanism, among others. Targeting heterogeneous polygenic profiles of individuals at high risks of complex traits is promising for the translation of genetic discoveries to health care. [ABSTRACT FROM AUTHOR]

The association between IGF-1 levels and mortality in humans is complex with low levels being associated with both low and high mortality. The present meta-analysis investigates this complex relationship between IGF-1 and all-cause mortality in prospective cohort studies. A systematic literature search was conducted in PubMed/MEDLINE, Scopus, and Cochrane Library up to September 2019. Published studies were eligible for the meta-analysis if they had a prospective cohort design, a hazard ratio (HR) and 95% confidence interval (CI) for two or more categories of IGF-1 and were conducted among adults. A random-effects model with a restricted maximum likelihood heterogeneity variance estimator was used to find combined HRs for all-cause mortality. Nineteen studies involving 30,876 participants were included. Meta-analysis of the 19 eligible studies showed that with respect to the low IGF-1 category, higher IGF-1 was not associated with increased risk of all-cause mortality (HR = 0.84, 95% CI = 0.68-1.05). Dose-response analysis revealed a U-shaped relation between IGF-1 and mortality HR. Pooled results comparing low vs. middle IGF-1 showed a significant increase of all-cause mortality (HR = 1.33, 95% CI = 1.14-1.57), as well as comparing high vs. middle IGF-1 categories (HR = 1.23, 95% CI = 1.06-1.44). Finally, we provide data on the association between IGF-1 levels and the intake of proteins, carbohydrates, certain vitamins/minerals, and specific foods. Both high and low levels of IGF-1 increase mortality risk, with a specific 120-160 ng/ml range being associated with the lowest mortality. These findings can explain the apparent controversy related to the association between IGF-1 levels and mortality. [ABSTRACT FROM AUTHOR]

Background: Genetic risk factors have been explored extensively for late onset Alzheimer's Disease (LOAD). The largest meta‐analysis GWAS studies to date (Bellenguez et al., 2022) identified 83 single nucleotide polymorphisms (SNPs) associated with LOAD in the general population. The Long Life Family Study (LLFS) is aimed to identify factors associated with familial longevity and healthy aging by examining US and Danish families. Our earlier studies have shown that LLFS families are at lower risk of several age‐related diseases, including LOAD. Here, we will: (1) compare allele frequencies and effect sizes of the identified meta‐GWAS variants against those in LLFS; and (2) assess whether a polygenic risk score (PRS) based on meta‐GWAS variants differs between LOAD vs. cognitively healthy in LLFS. Method: We examined LLFS participants who were Non‐Hispanic Whites, had available cognitive and whole genome sequencing (WGS) (n = 4,220). Allele frequencies were estimated based on founders only. Association analyses were performed via logistic regression using Wald test and adjusting for sex, age, site, education, first principal components, and the genetic relationship matrix. PRS was calculated using a weighted formula, and to account for family structure, means for each status per family were obtained. Result: Independent of LOAD status, 13 SNPs had significantly different allele frequencies between the two studies. Minor allele frequencies of 10 of the SNPs were lower in LLFS when compared with Bellenguez et al. When examining the relations between LOAD and the 77 available SNPs, only five variants appeared to be associated in LLFS. The direction of association differed for two of the SNPs. Lastly, estimated PRS scores did not differ by LOAD status (affected vs unaffected: ‐0.059 vs. ‐0.054, respectively). Conclusion: Here we show that variants associated with LOAD in the general population were not necessarily associated with LOAD in in the LLFS cohort, a cohort ascertained for familial healthy aging. When estimating disease risk using genetic markers, as expected, ascertainment needs to be taken into consideration. [ABSTRACT FROM AUTHOR]

Aging is a biological process linked to specific patterns and changes in the epigenome. We hypothesize that age‐related variation in the DNA methylome could reflect cumulative environmental modulation to the epigenome which could impact epigenomic instability and survival differentially by sex. To test the hypothesis, we performed sex‐stratified epigenome‐wide association studies on age‐related intra‐pair DNA methylation discordance in 492 twins aged 56–80 years. We identified 3084 CpGs showing increased methylation variability with age (FDR < 0.05, 7 CpGs with p < 1e‐07) in male twins but no significant site found in female twins. The results were replicated in an independent cohort of 292 twins aged 30–74 years with 37% of the discovery CpGs successfully replicated in male twins. Functional annotation showed that genes linked to the identified CpGs were significantly enriched in signaling pathways, neurological functions, extracellular matrix assembly, and cancer. We further explored the implication of discovery CpGs on individual survival in an old cohort of 224 twins (220 deceased). In total, 264 CpGs displayed significant association with risk of death in male twins. In female twins, 175 of the male discovery CpGs also showed non‐random correlation with mortality. Intra‐pair comparison showed that majority of the discovery CpGs have higher methylation in the longer‐lived twins suggesting that loss of DNA methylation during aging contributes to increased risk of death which is more pronounced in male twins. In conclusion, age‐related epigenomic instability in the DNA methylome is more evident in males than in females and could impact individual survival and contribute to sex difference in human lifespan. [ABSTRACT FROM AUTHOR]

Privileged by rapid increase in available epigenomic data, epigenome‐wide association studies (EWAS) are to make a profound contribution to understand the molecular mechanism of DNA methylation in cognitive aging. Current statistical methods used in EWAS are dominated by models based on multiple assumptions, for example, linear relationship between molecular profiles and phenotype, normal distribution for the methylation data and phenotype. In this study, we applied an assumption‐free method, the generalized correlation coefficient (GCC), and compare it to linear models, namely the linear mixed model and kinship model. We use DNA methylation associated with a cognitive score in 400 and 206 twins as discovery and replication samples respectively. DNA methylation associated with cognitive function using GCC, linear mixed model, and kinship model, identified 65 CpGs (p < 1e‐04) from discovery sample displaying both nonlinear and linear correlations. Replication analysis successfully replicated 9 of these top CpGs. When combining results of GCC and linear models to cover diverse patterns of relationships, we identified genes like KLHDC4, PAPSS2, and MRPS18B as well as pathways including focal adhesion, axon guidance, and some neurological signaling. Genomic region‐based analysis found 15 methylated regions harboring 11 genes, with three verified in gene expression analysis, also the 11 genes were related to top functional clusters including neurohypophyseal hormone and maternal aggressive behaviors. The GCC approach detects valuable methylation sites missed by traditional linear models. A combination of methylation markers from GCC and linear models enriched biological pathways sensible in neurological function that could implicate cognitive performance and cognitive aging. [ABSTRACT FROM AUTHOR]

The familial resemblance in length of adult life is very modest. Studies of parent‐offspring and twins suggest that exceptional health and survival have a stronger genetic component than lifespan generally. To shed light on the underlying mechanisms, we collected information on Danish long‐lived siblings (born 1886–1938) from 659 families, their 5379 offspring (born 1917–1982), and 10,398 grandchildren (born 1950–2010) and matched background population controls through the Danish 1916 Census, the Civil Registration System, the National Patient Register, and the Register of Causes of Death. Comparison with the background, population revealed consistently lower occurrence of almost all disease groups and causes of death in the offspring and the grandchildren. The expected incidence of hospitalization for mental and behavioral disorders was reduced by half in the offspring (hazard ratio 0.53, 95% confidence interval 0.45–0.62) and by one‐third in the grandchildren (0.69, 0.61–0.78), while the numbers for tobacco‐related cancer were 0.60 (0.51–0.70) and 0.71 (0.48–1.05), respectively. Within‐family analyses showed a general, as opposed to specific, lowering of disease risk. Early parenthood and divorce were markedly less frequent in the longevity‐enriched families, while economic and educational differences were small to moderate. The longevity‐enriched families in this study have a general health advantage spanning three generations. The particularly low occurrence of mental and behavioral disorders and tobacco‐related cancers together with indicators of family stability and only modest socioeconomic advantage implicate behavior as a key mechanism underlying familial aggregation of exceptional health and survival. [ABSTRACT FROM AUTHOR]

Genome‐wide scans have shown that common risk alleles for orofacial clefts (OFC) tend to be located in noncoding regulatory elements and cumulatively explain only part of the heritability of OFCs. Low‐frequency variants may account for some of the "missing" heritability. Therefore, we scanned low‐frequency variants located within putative craniofacial enhancers to identify novel OFC risk variants and implicate new regulatory elements in OFC pathogenesis. Analyses were performed in a multiethnic sample of 1,995 cases of cleft lip with or without cleft palate (CL/P), 221 cases with cleft palate (CP) only, and 1,576 unaffected controls. One hundred and nineteen putative craniofacial enhancers identified from ChIP‐Seq studies in craniofacial tissues or cell lines contained multiple low‐frequency (0.01–1%) variants, which we genotyped in participants using a custom Illumina panel. Two complementary statistical approaches, sequence kernel association test and combined multivariate and collapsing, were used to test association of the aggregated low‐frequency variants across each enhancer region with CL/P and CP. We discovered a significant association between CP and a branchial arch enhancer near FOXP1 (mm60; p‐value = .0002). Additionally, we observed a suggestive association between CL/P and a forebrain enhancer near FOXE1 (hs1717; p‐value = .001). These findings suggest that low‐frequency variants in craniofacial enhancer regions contribute to the complex etiology of nonsyndromic OFCs. [ABSTRACT FROM AUTHOR]

Summary: In human longevity studies, single nucleotide polymorphism (SNP) analysis identified a large number of genetic variants with small effects, yet not easily replicable in different populations. New insights may come from the combined analysis of different SNPs, especially when grouped by metabolic pathway. We applied this approach to study the joint effect on longevity of SNPs belonging to three candidate pathways, the insulin/insulin‐like growth factor signalling (IIS), DNA repair and pro/antioxidant. We analysed data from 1,058 tagging SNPs in 140 genes, collected in 1825 subjects (1,089 unrelated nonagenarians from the Danish 1905 Birth Cohort Study and 736 Danish controls aged 46–55 years) for evaluating synergic interactions by SNPsyn. Synergies were further tested by the multidimensional reduction (MDR) approach, both intra‐ and interpathways. The best combinations (FDR<0.0001) resulted those encompassing IGF1R‐rs12437963 and PTPN1‐rs6067484, TP53‐rs2078486 and ERCC2‐rs50871, TXNRD1‐rs17202060 and TP53‐rs2078486, the latter two supporting a central role of TP53 in mediating the concerted activation of the DNA repair and pro‐antioxidant pathways in human longevity. Results were consistently replicated with both approaches, as well as a significant effect on longevity was found for the GHSR gene, which also interacts with partners belonging to both IIS and DNA repair pathways (PAPPA, PTPN1, PARK7, MRE11A). The combination GHSR‐MREA11, positively associated with longevity by MDR, was further found influencing longitudinal survival in nonagenarian females (p = .026). Results here presented highlight the validity of SNP‐SNP interactions analyses for investigating the genetics of human longevity, confirming previously identified markers but also pointing to novel genes as central nodes of additional networks involved in human longevity. [ABSTRACT FROM AUTHOR]

The biological relatives of offspring with nonsyndromic orofacial clefts have been shown to exhibit distinctive facial features, including excess asymmetry, which are hypothesized to indicate the presence of genetic risk factors. The significance of excess soft tissue nasal asymmetry in at‐risk relatives is unclear and was examined in the present study. Our sample included 164 unaffected parents from families with a history of orofacial clefting and 243 adult controls. Geometric morphometric methods were used to analyze the coordinates of 15 nasal landmarks collected from three‐dimensional facial surface images. Following generalized Procrustes analysis, Procrustes ANOVA and MANOVA tests were applied to determine the type and magnitude of nasal asymmetry present in each group. Group differences in mean nasal asymmetry were also assessed via permutation testing. We found that nasal asymmetry in both parents and controls was directional in nature, although the magnitude of the asymmetry was greater in parents. This was confirmed with permutation testing, where the mean nasal asymmetry was significantly different (p < .0001) between parents and controls. The asymmetry was greatest for midline structures and the nostrils. When subsets of parents were subsequently analyzed and compared (parents with bilateral vs. unilateral offspring; parents with left vs. right unilateral offspring), each group showed a similar pattern of asymmetry and could not be distinguished statistically. Thus, the side of the unilateral cleft (right vs. left) in offspring was not associated with the direction of the nasal asymmetry in parents. [ABSTRACT FROM AUTHOR]

Abstract: Aim: To explore the genetic and environmental influences on cardiovascular risk factors (CVRF) and cognitive function in the world's largest and rapidly aging Chinese population. Methods: Cognitive function and CVRF, including body mass index, systolic blood pressure, diastolic blood pressure, pulse pressure, glucose, total cholesterol, triglyceride, high‐density lipoprotein cholesterol (HDLC) and low‐density lipoprotein cholesterol were measured in 379 complete twin pairs. Univariate and bivariate twin models were fitted to estimate the genetic and environmental components in the variance and covariance of CVRF and cognition. Results: Mild‐to‐high heritability was estimated for CVRF and cognition (0.27–0.74). Unique environmental factors showed low‐to‐moderate contributions (0.23–0.56). Only HDLC presented significant common environmental contribution (0.50). Bivariate analysis showed significantly negative genetic correlations (rG) between cognition and systolic blood pressure (rG = −0.56), diastolic blood pressure (rG = −0.42), pulse pressure (rG = −0.45), and positive genetic correlations between cognition and total cholesterol (rG = 0.33), triglyceride (rG = 0.23) and HDLC (rG = 0.41). HDLC and cognition presented a unique environmental correlation (rE = −0.13), but in the opposite direction. Conclusions: Cognitive function was genetically related to systolic blood pressure, diastolic blood pressure, pulse pressure, total cholesterol, triglyceride and HDLC with a negative or positive direction. Cognition and HDLC might share part of a similar unique environmental factor. Geriatr Gerontol Int 2018; 18: 352–359. [ABSTRACT FROM AUTHOR]

Introduction We examined the association between cognitive ability in young adulthood and dementia in Danish men, brothers, and male twins. Methods In total, 666,986 men born between 1939 and 1959 were identified for dementia diagnosis in national registries from 1969 to 2016. The association between cognitive ability from draft board examination and dementia was examined using Cox regression. Results During a 44-year follow-up, 6416 (0.96%) men developed dementia, 1760 (0.26%) and 970 (0.15%) of which were classified as Alzheimer's and vascular dementia, respectively. Low cognitive ability was associated with increased risk of dementia (hazard ratio [HR] per SD decrease 1.33 [95% confidence interval {CI} = 1.30–1.35]) with the strongest associations for vascular dementia (HR per SD decrease 1.47 [95% CI = 1.31–1.56]) and a weaker for Alzheimer's disease (HR per SD decrease 1.07 [95% CI = 1.03–1.13]). The intrabrother and twin analyses (taking shared family factors into account) showed attenuated risk estimates but with wide CIs. Discussion Low early-life cognitive ability increases the risk of dementia before the age of 78 years. The association is partly explained by shared family factors. [ABSTRACT FROM AUTHOR]

Nonsyndromic orofacial clefts (OFCs) are complex traits characterized by multifactorial inheritance and wide phenotypic variability. Numerous studies have shown subtle differences in the faces of unaffected relatives from cleft families compared to controls, the implication being that such outward differences are an incomplete expression reflecting an underlying genetic predisposition. Twins discordant for OFCs provide a unique opportunity to further test this idea, as the unaffected co-twin shares on average 50% (for dizygotic twins) and 100% (for monozygotic twins) of the genetic risk factors as the affected twin. We used 3D surface imaging and spatially-dense morphometry to compare facial shape in a sample of 44 unaffected co-twins and age- and sex-matched unaffected controls ( n = 241). Unaffected co-twins showed statistically significant differences in the midface, lateral upper face, and forehead regions, compared to controls. Furthermore, co-twins were characterized by a distinct pattern of midfacial retrusion, broader upper faces, and greater protrusion of the mandible and brow ridges. This same general facial pattern was shown in both unaffected monozygotic and dizygotic co-twin subsets. These results provide additional support that altered facial shape is a phenotypic marker for OFC susceptibility. [ABSTRACT FROM AUTHOR]

Human longevity is a complex phenotype influenced by genetic and environmental components. Unraveling the contribution of genetic vs. nongenetic factors to longevity is a challenging task. Here, we conducted a large-scale RNA-sequencing-based expression quantitative trait loci study ( eQTL) with subsequent heritability analysis. The investigation was performed on blood samples from 244 individuals from Germany and Denmark, representing various age groups including long-lived subjects up to the age of 104 years. Our eQTL-based approach revealed for the first time that human longevity is associated with a depletion of metabolic pathways in a genotype-dependent and independent manner. Further analyses indicated that 20% of the differentially expressed genes are influenced by genetic variants in cis. The subsequent study of twins showed that the transcriptional activity of a third of the differentially regulated genes is heritable. These findings suggest that longevity-associated biological processes such as altered metabolism are, to a certain extent, also the driving force of longevity rather than just a consequence of old age. [ABSTRACT FROM AUTHOR]

ABSTRACT Genetic and environmental determinants of skeletal phenotypes such as bone mineral density (BMD) may converge through the epigenome, providing a tool to better understand osteoporosis pathophysiology. Because the epigenetics of BMD have been largely unexplored in humans, we performed an epigenome-wide association study (EWAS) of BMD. We undertook a large-scale BMD EWAS using the Infinium HumanMethylation450 array to measure site-specific DNA methylation in up to 5515 European-descent individuals ( NDiscovery = 4614, NValidation = 901). We associated methylation at multiple cytosine-phosphate-guanine (CpG) sites with dual-energy X-ray absorptiometry (DXA)-derived femoral neck and lumbar spine BMD. We performed sex-combined and stratified analyses, controlling for age, weight, smoking status, estimated white blood cell proportions, and random effects for relatedness and batch effects. A 5% false-discovery rate was used to identify CpGs associated with BMD. We identified one CpG site, cg23196985, significantly associated with femoral neck BMD in 3232 females ( p = 7.9 × 10−11) and 4614 females and males ( p = 3.0 × 10−8). cg23196985 was not associated with femoral neck BMD in an additional sample of 474 females ( p = 0.64) and 901 males and females ( p = 0.60). Lack of strong consistent association signal indicates that among the tested probes, no large-effect epigenetic changes in whole blood associated with BMD, suggesting future epigenomic studies of musculoskeletal traits measure DNA methylation in a different tissue with extended genome coverage. © 2017 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Background: Oral clefts (OCs) are among the most common congenital malformations and can have a large impact on the life of the affected individual. Research findings regarding the psychological and psychosocial consequences of OC are inconclusive. Methods: Using Danish nationwide registers, we investigated redeemed prescriptions of psychotropic medication during 1996 to 2012 and visits to psychiatrists and psychologists during 1996 to 2011 among individuals born with nonsyndromic OC in Denmark between 1936 and 2009 and a comparison cohort of individuals without OC. This includes 8244 individuals with OC and 82,665 individuals without OC. Results: The Cox regression analysis revealed 12% (95% confidence interval [CI], 7 to 16%) increased risk of using any psychotropic medication for individuals with OC. When examining by cleft type, higher risks for medication use were observed in individuals with cleft lip and palate (CLP) or cleft palate (CP) only. The largest increased relative risk was found for use of antipsychotics and stimulants for individuals with CP followed by use of antipsychotics for individuals with CLP. We found increased risk of visits to psychiatrists for individuals with CP and no increased risk for visits to psychologists for either group. Conclusions: This study indicates that a small group of individuals with nonsyndromic OC, in particular those with palatal involvement, have greater risk of using psychotropic medications. However, elevated use was also observed among younger individuals with cleft lip (CL) only. There seems to be only a modest increase in visits to health professionals for psychological reasons. Undiagnosed syndromes (e.g., 22q11 deletion syndrome), may, however, contribute to an overestimation of the associations. [ABSTRACT FROM AUTHOR]

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a group of common human birth defects with complex etiology. Although genome-wide association studies have successfully identified a number of risk loci, these loci only account for about 20% of the heritability of orofacial clefts. The 'missing' heritability may be found in rare variants, copy number variants, or interactions. In this study, we investigated the role of low-frequency variants genotyped in 1995 cases and 1626 controls on the Illumina HumanCore + Exome chip. We performed two statistical tests, Sequence Kernel Association Test (SKAT) and Combined Multivariate and Collapsing (CMC) method using two minor allele frequency cutoffs (1% and 5%). We found that a burden of low-frequency coding variants in N4BP2, CDSN, PRTG, and AHRR were associated with increased risk of NSCL/P. Low-frequency variants in other genes were associated with decreased risk of NSCL/P. These results demonstrate that low-frequency variants contribute to the genetic etiology of NSCL/P. [ABSTRACT FROM AUTHOR]

Purpose In observational studies, non-response can limit representativity and introduce bias. We aimed to investigate the longitudinal changes in the number of used drugs among complete responders, partial responders, and non-responders in a whole birth cohort of Danish nonagenarians participating in a longitudinal survey. Methods We obtained prescription data on all individuals born in 1905 and living in Denmark when the Danish 1905 cohort study was initiated in 1998 ( n = 3600) using the Danish National Prescription Registry. Drug use was assessed for complete responders, non-responders at baseline, and partial responders (i.e., dropouts) in the 4-month period preceding each wave of the study (1998, 2000, 2003, and 2005), that is, as the cohort aged from 92-93 to 99-100 years. Results Complete responders, non-responders, and partial responders used a similar number of drugs at baseline, on average 4.4, increasing to 5.6 at the age of 99-100 years. In all groups, the number of used drugs increased over time; partial responders had the largest increase of 0.39 drugs per year (95% confidence interval (CI): 0.33-0.44) compared with 0.32 (95%CI: 0.27-0.37) and 0.30 (95%CI: 0.25-0.35) in the other groups. Furthermore, the most frequently used drug classes (e.g., loop diuretics and paracetamol) and the drug classes with the largest change (e.g., increase: laxatives and paracetamol; decrease: benzodiazepines) were similar across response groups. Conclusions The number of used drugs increased in all response groups between the age of 92 and 100 years. In this study, drug use among complete responders was representative of the general drug use in the entire cohort. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objectives To determine the longitudinal development of drug use in very old adults. Design Longitudinal cohort study with waves in 1998, 2000, 2002, and 2005. Setting Nationwide study in Denmark. Participants All living Danes born in 1905 were approached in 1998; 2,262 responded at baseline. Measurements Self-reported use of regularly taken drugs. Mean and median number of drugs and growth curve models were used to identify the change in number of drugs as the cohort aged from 92 to 100. Results The within-person use of drugs increased with age for women (0.19 per year; 95% confidence interval ( CI) = 0.15-0.24) and men (0.15 per year; 95% CI = 0.06-0.24). Persons leaving the study prematurely had higher baseline values and a steeper increase in their annual use of drugs. The population-level mean number of drugs increased from baseline (3.6 drugs) to the first follow-up (4.1 drugs) but thereafter remained stable at approximately 4 drugs. Women used more drugs than men at all waves. Conclusion In this first longitudinal study of drug use in nonagenarians, individuals used an increasing number of drugs as they aged. This increase is difficult to detect in cross-sectional analyses of the population-level mean. More efforts to understand what is reasonable prescribing at these older ages are needed. [ABSTRACT FROM AUTHOR]

Objectives To investigate the association between mortality and heritability of a rescaled Fried frailty index, the Scale of Aging Vigor in Epidemiology ( SAVE), to determine its value for genetic analyses. Design Longitudinal, community-based cohort study. Setting The Long Life Family Study ( LLFS) in the United States and Denmark. Participants Long-lived individuals (N = 4,875, including 4,075 genetically related individuals) and their families (N = 551). Measurements The SAVE was administered to 3,599 participants and included weight change, weakness (grip strength), fatigue (questionnaire), physical activity (days walked in prior 2 weeks), and slowness (gait speed); each component was scored 0, 1, or 2 using approximate tertiles, and summed (range 0 (vigorous) to 10 (frail)). Heritability was determined using a variance component-based family analysis using a polygenic model. Association with mortality in the proband generation (N = 1,421) was calculated using Cox proportional hazards mixed-effect models. Results Heritability of the SAVE was 0.23 ( P < .001) overall (n = 3,599), 0.31 ( P < .001) in probands (n = 1,479), and 0.26 ( P < .001) in offspring (n = 2,120). In adjusted models, higher SAVE scores were associated with higher mortality (score 5-6: hazard ratio ( HR) = 2.83, 95% confidence interval ( CI) = 1.46-5.51; score 7-10: HR = 3.40, 95% CI = 1.72-6.71) than lower scores (0-2). Conclusion The SAVE was associated with mortality and was moderately heritable in the LLFS, suggesting a genetic component to age-related vigor and frailty and supporting its use for further genetic analyses. [ABSTRACT FROM AUTHOR]

Human longevity is characterized by a remarkable lack of confirmed genetic associations. Here, we report on the identification of a novel locus for longevity in the RAD50/ IL13 region on chromosome 5q31.1 using a combined European sample of 3208 long-lived individuals ( LLI) and 8919 younger controls. First, we performed a large-scale association study on 1458 German LLI (mean age 99.0 years) and 6368 controls (mean age 57.2 years) by targeting known immune-associated loci covered by the Immunochip. The analysis of 142 136 autosomal single nucleotide polymorphisms ( SNPs) revealed an Immunochip-wide significant signal ( PImmunochip = 7.01 × 10-9) for the SNP rs2075650 in the TOMM40/ APOE region, which has been previously described in the context of human longevity. To identify novel susceptibility loci, we selected 15 markers with PImmunochip < 5 × 10-4 for replication in two samples from France (1257 LLI, mean age 102.4 years; 1811 controls, mean age 49.1 years) and Denmark (493 LLI, mean age 96.2 years; 740 controls, mean age 63.1 years). The association at SNP rs2706372 replicated in the French study collection and showed a similar trend in the Danish participants and was also significant in a meta-analysis of the combined French and Danish data after adjusting for multiple testing. In a meta-analysis of all three samples, rs2706372 reached a P-value of PImmunochip+Repl = 5.42 × 10−7 ( OR = 1.20; 95% CI = 1.12-1.28). SNP rs2706372 is located in the extended RAD50/ IL13 region. RAD50 seems a plausible longevity candidate due to its involvement in DNA repair and inflammation. Further studies are needed to identify the functional variant(s) that predispose(s) to a long and healthy life. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the risk of early discontinuation of metformin as a proxy for intolerance, associated with use of drugs known to inhibit transporters involved in metformin distribution. We analysed all incident users of metformin in Denmark between 2000 and 2012 (n = 132,221) and in a cohort of US patients (n = 296,903). Risk of early discontinuation of metformin was assessed using adjusted logistic regression for 28 drugs putatively inhibiting metformin transporters and four negative controls. Increased odds ratio of early discontinuation of metformin was only associated with codeine, an inhibitor of organic cation transporter 1 in both cohorts [adjusted odds ratio ( OR) in Danish cohort (95% CI): 1.13 (1.02-1.26), adjusted OR in American cohort (95% CI): 1.32 (1.19-1.47)]. The remaining drugs were not associated with increased odds ratio of early discontinuation and, surprisingly, four drugs were associated with a decreased risk. These findings indicate that codeine use may be associated with risk of early discontinuation of metformin and could be used as a basis for further investigation. [ABSTRACT FROM AUTHOR]

An epigenetic profile defining the DNA methylation age ( DNAm age) of an individual has been suggested to be a biomarker of aging, and thus possibly providing a tool for assessment of health and mortality. In this study, we estimated the DNAm age of 378 Danish twins, age 30-82 years, and furthermore included a 10-year longitudinal study of the 86 oldest-old twins (mean age of 86.1 at follow-up), which subsequently were followed for mortality for 8 years. We found that the DNAm age is highly correlated with chronological age across all age groups ( r = 0.97), but that the rate of change of DNAm age decreases with age. The results may in part be explained by selective mortality of those with a high DNAm age. This hypothesis was supported by a classical survival analysis showing a 35% (4-77%) increased mortality risk for each 5-year increase in the DNAm age vs. chronological age. Furthermore, the intrapair twin analysis revealed a more-than-double mortality risk for the DNAm oldest twin compared to the co-twin and a 'dose-response pattern' with the odds of dying first increasing 3.2 (1.05-10.1) times per 5-year DNAm age difference within twin pairs, thus showing a stronger association of DNAm age with mortality in the oldest-old when controlling for familial factors. In conclusion, our results support that DNAm age qualifies as a biomarker of aging. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives To determine whether simple functional indicators are predictors of survival prognosis in very old adults. Design In-person survey conducted over a 3-month period in 1998; assessment of survival over a 15-year follow-up period. Setting Denmark. Participants All 3,600 Danes born in 1905 and living in Denmark in 1998, were invited to participate regardless of residence and health; 2,262 (63%) participated in the survey: 1,814 (80.2%) in person and 448 (19.8%) through a proxy. Measurements Socioeconomic factors, medications and diseases, activities of daily living, physical performance, cognition, depression symptomatology, self-rated health, and all-cause mortality, evaluated as average remaining lifespan and chance of surviving to 100 years. Results Men aged 92 to 93 had an overall 6.0% chance of surviving to 100 years, whereas the chance for women was 11.4%. Being able to rise without use of hands increased the chance for men to 11.2% (95% confidence interval (CI) = 7.7-14.7) and for women to 22.0% (95% CI = 18.9-25.1). When combining this with a Mini-Mental State Examination (MMSE) scores from 28 to 30, the chances were 21.7% (95% CI = 11.5-31.9) for men and 34.2% (95% CI = 24.8-43.5) for women. Conclusion Chair stand score combined with MMSE score is a quick and easy way to estimate overall chance of survival in very old adults, which is particularly relevant when treatment with potential side effects for nonacute diseases is considered. [ABSTRACT FROM AUTHOR]

Background Isolated tremor in the elderly is commonly diagnosed as essential tremor (ET). The prevalence of tremor increases steeply with increasing age, whereas hereditary tremor is becoming less common. Moreover, late-manifesting tremor seems to be associated with dementia and earlier mortality. We hypothesize that different entities underlie tremor in the elderly. Methods Two thousand four hundred forty-eight subjects from the Longitudinal Study of Aging Danish Twins older than 70 y answered screening questions for ET in 2001. Two thousand fifty-six (84%) participants drew Archimedes spirals to measure their tremor severity, and classical aging phenotypes were assessed. A subgroup of 276 individuals fulfilling either screening criteria for ET or being controls were personally assessed. Medications and mortality data are available. Results The spiral score increased with age. The spiral score correlated with tremor severity. For the whole cohort, mortality was significantly correlated with the spiral score, and higher spiral scores were associated with lower physical and cognitive functioning. Multivariate analysis identified higher spiral scores as an independent risk factor for mortality. In contrast, the ET patients did not show an increased but rather a lower mortality rate although it was not statistically significant. Consistent with a slower than normal aging, they were also physically and cognitively better functioning than controls. Conclusions Because incident tremors beyond 70 y of age show worse aging parameters and mortality than controls and ET, we propose to label it 'aging-related tremor' (ART). This tremor starts later in life and is accompanied by subtle signs of aging both cognitively and physically. More detailed clinical features and pathogenesis warrant further assessment. © 2015 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis To estimate the risk of surgically treated middle ear cholesteatoma in individuals with a nonsyndromic orofacial cleft and in their siblings compared with the general population. Study Design Historical cohort study. Methods Using the unique civil registration number for linkage, data from three national registers were used for the Danish 1936-2009 birth cohorts. Hazard ratios (HRs) were estimated with Cox regression analyses using age as the underlying time variable. Individuals were followed from January 1, 1977 until time of surgically treated cholesteatoma, and censored at emigration, death, or end of follow-up (December 31, 2010). Results A total of 8,593 individuals with nonsyndromic orofacial cleft and 6,989 siblings were identified, undergoing 201 and 21 first-time cholesteatoma surgeries, respectively. A 5% random sample of the Danish population comprising 249,708 persons without an orofacial cleft was created, and 175,724 siblings to these persons were identified. These controls underwent 485 and 332 first-time cholesteatoma surgeries, respectively. For individuals with cleft lip and palate the HR for cholesteatoma surgery was 14 (95% confidence interval [CI], 12-18) and for individuals with cleft palate the HR was 20 (95% CI, 16-24) when compared with the random sample. In siblings of individuals with cleft palate, the HR for cholesteatoma surgery was 2.1 (95% CI, 1.1-4.1) when compared with siblings of the random sample. Conclusions A 20-fold increase in the risk of cholesteatoma was found in individuals with cleft palate, whereas cleft lip did not pose a risk of cholesteatoma. Furthermore, the study indicates an increased risk of cholesteatoma in unaffected siblings of individuals with cleft palate. Level of Evidence 2b Laryngoscope, 125:1225-1229, 2015 [ABSTRACT FROM AUTHOR]

FOXO3A variation has repeatedly been reported to associate with human longevity, yet only few studies have investigated whether FOXO3A variation also associates with aging-related traits. Here, we investigate the association of 15 FOXO3A tagging single nucleotide polymorphisms (SNPs) in 1088 oldest-old Danes (age 92-93) with 4 phenotypes known to predict their survival: cognitive function, hand grip strength, activity of daily living (ADL), and self-rated health. Based on previous studies in humans and foxo animal models, we also explore self-reported diabetes, cancer, cardiovascular disease, osteoporosis, and bone (femur/ spine/hip/wrist) fracture. Gene-based testing revealed significant associations of FOXO3A variation with ADL (P = 0.044) and bone fracture (P = 0.006). The single-SNP statistics behind the genebased analysis indicated increased ADL (decreased disability) and reduced bone fracture risk for carriers of the minor alleles of 8 and 10 SNPs, respectively. These positive directions of effects are in agreement with the positive effects on longevity previously reported for these SNPs. However, when correcting for the test of 9 phenotypes by Bonferroni correction, bone fracture showed borderline significance (P = 0.054), while ADL did not (P = 0.396). Although the single-SNP associations did not formally replicate in another study population of oldest-old Danes (n = 1279, age 94-100), the estimates were of similar direction of effect as observed in the Discovery sample. A pooled analysis of both study populations displayed similar or decreased sized P-values for most associations, hereby supporting the initial findings. Nevertheless, confirmation in additional study populations is needed. [ABSTRACT FROM AUTHOR]

Background Few human cohort studies on anesthesia-related neurotoxicity and the developing brain have focused on and compared specific surgeries and conditions. These studies cannot disentangle the effects of anesthesia from those of the surgery and underlying conditions. This study aimed at assessing the impact of specific neurosurgical conditions and procedures in infancy on mortality and academic achievements in adolescence. Methods A nationwide unselected register-based follow-up study of the Danish birth cohorts 1986-1990 compared academic performances of all children having undergone neurosurgeries as infants with a randomly selected, age-matched 5% sample of the same cohorts. The two groups were compared regarding mortality prior to June 1st, 2006, average test scores at ninth grade, and finally the proportion of children not attaining test scores. Results The exposure group comprised 228 and the control group 14 698 individuals. Hydrocephalus ( n = 130), craniotomy ( n = 43), and myelomeningocele/encephalocele children ( n = 55) had a higher mortality (18.5.0%, 18.6%, and 7.3%, respectively) vs controls (1.3%; P < 0.00001, P < 0.00001, and P = 0.0052, respectively). Average test scores were significantly lower than controls in hydrocephalus and craniotomy ( P = 0.0043 and P = 0.0077) but not myelomeningocele/encephalocele children ( P = 0.2785); the proportion of available test scores were significantly lower in all three groups (40.8%, 60.0%, and 67.3%, respectively) vs 86.8% in controls ( P < 0.00001, P = 0.000077, and P = 0.000064). Conclusion Neurosurgery in infancy was associated with high mortality and significantly impaired academic achievements in adolescence. When studying anesthesia-related neurotoxicity and the developing brain, focus on specific surgeries/conditions is important. Pooling of major/minor conditions and major/minor surgeries should be avoided. [ABSTRACT FROM AUTHOR]

To re-examine the correlation between mt DNA variability and longevity, we examined mt DNAs from samples obtained from over 2200 ultranonagenarians (and an equal number of controls) collected within the framework of the GEHA EU project. The samples were categorized by high-resolution classification, while about 1300 mt DNA molecules (650 ultranonagenarians and an equal number of controls) were completely sequenced. Sequences, unlike standard haplogroup analysis, made possible to evaluate for the first time the cumulative effects of specific, concomitant mt DNA mutations, including those that per se have a low, or very low, impact. In particular, the analysis of the mutations occurring in different OXPHOS complex showed a complex scenario with a different mutation burden in 90+ subjects with respect to controls. These findings suggested that mutations in subunits of the OXPHOS complex I had a beneficial effect on longevity, while the simultaneous presence of mutations in complex I and III (which also occurs in J subhaplogroups involved in LHON) and in complex I and V seemed to be detrimental, likely explaining previous contradictory results. On the whole, our study, which goes beyond haplogroup analysis, suggests that mitochondrial DNA variation does affect human longevity, but its effect is heavily influenced by the interaction between mutations concomitantly occurring on different mt DNA genes. [ABSTRACT FROM AUTHOR]

Objective Hyperthyroidism has been suggested to adversely affect cognitive function. However, this association could also be caused by genetic and environmental factors affecting both the development of hyperthyroidism and cognitive functioning. By investigating twin pairs discordant for hyperthyroidism, this potential confounding can be minimized. The aim of the study was to examine whether hyperthyroidism is associated with long-term cognitive dysfunction. Design Twin case-control study. Patients Twin pairs discordant for hyperthyroidism were identified by record linkage between The Danish National Patient Registry and 3036 twin pairs from The Danish Twin Registry, who had participated in nationwide surveys on health conditions. Measurements Among other investigations, survey participants had carried out cognitive tests including a Mini-mental state examination ( MMSE) and six separate cognitive tests. Based on five of the tests, a composite cognitive score was calculated. Results Fifty-five of 3036 twin pairs were discordant for hyperthyroidism. The mean time from diagnosis until survey participation was 7·3 years (range: 0-24·1 years). In both the intrapair and individual-level analyses, the hyperthyroid twin scored significantly better in the MMSE than did the healthy co-twin ( P = 0·023 and P = 0·038, respectively). The same tendency was found in the other cognitive tests, and after analysing twins diagnosed with hyperthyroidism more than 2 years before participating, although none were statistically significant. Conclusion Utilizing discordant twin pairs to control for genetic as well as early environmental factors, we could not demonstrate any clinically relevant negative impact of previous hyperthyroidism on long-term cognitive function. [ABSTRACT FROM AUTHOR]

ABSTRACT Low birth weight (BW) has been associated with poor bone health in adulthood. The aim of this study was to investigate the association between BW and bone mass and metabolism in adult BW-discordant monozygotic (MZ) twins. A total of 153 BW-extremely discordant MZ twin pairs were recruited from the Danish Twin Registry. Serum vitamin D (25-hydroxyvitamin D [25OHD]) and bone turnover markers (BTMs) amino-terminal propeptide of type I procollagen (P1NP), pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (1CTP), and cross-linked C-telopeptide (CTX) were quantified. Femoral neck (FN), total hip (TH), lumbar spine (LS), and whole-body (WB) bone mineral density (BMD) (ie, FN-BMD, TH-BMD, LS-BMD, and WB-BMD, respectively) were measured using dual-energy X-ray absorptiometry (DXA). Twins were studied as single individuals using regression analyses with or without adjustment for height, weight, age, sex, and intrapair correlation. Within-pair differences were assessed using Student's t test and fixed-regression models. BW was not associated with BTMs, LS-BMD, TH-BMD, FN-BMD, or WB-BMD, but BW was associated with WB-BMC, and WB-Area after adjustments. Compared to the co-twin, twins with the highest BW were heavier and taller in adulthood (mean differences ± SD): 3.0 ± 10.5 kg; 1.6 ± 2.6 cm; both p < 0.001). Within-pair analyses showed that LS-BMD, TH-BMD, and FN-BMD tended to be higher in twins with highest BW (for all: mean difference 0.01 ± 0.1 g/cm2; p = 0.08, 0.05, and 0.10, respectively). No difference was observed after adjustment for adult body size. Intrapair differences in BW were not associated with differences in any of the biochemical parameters or BMD. Small differences between twins in BMD were explained by dissimilarities in body size. These results suggest that BW and adult bone metabolism are unrelated. © 2013 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Background Immature animals exposed to anesthetics display apoptotic neurodegeneration with subsequent long-term cognitive dysfunctions. Young age at anesthetic exposure is believed to be critical, but human studies are scarce. This study investigated the association between exposure to surgery and anesthesia for pyloric stenosis ( PS) before 3 months of age and subsequent educational outcome in adolescence. Methods This nationwide unselected register-based follow-up study of the Danish birth cohorts 1986-1990 compared the educational outcome of all children having undergone surgery for PS before 3 months of age with a randomly selected, age-matched 5% sample of the same cohort. Primary analysis compared the average test scores at ninth grade adjusting for gender, birth weight, and parental age and education. Secondary analysis compared the proportions not attaining the test scores between the two groups. Results The exposure group comprised 779 and the control group consisted of 14 665 individuals. Although the exposure group performed lower than the control group (average score 0.17 lower, 95% CI: 0.08-0.25), after adjusting for known confounders, no statistically significant difference (−0.04, 95% CI: −0.09 to 0.08) between the 2 groups could be demonstrated. However, we found an odds ratio ( OR) for test score nonattainment-associated PS repair of 1.37 (95% CI: 1.11-1.68). Conclusion Children operated for PS before 3 months of age have educational performance tests similar to the background population at age 15-16 years after adjusting for known confounders. The higher nonattainment rate could suggest that a subgroup of PS children is developmentally disadvantaged. [ABSTRACT FROM AUTHOR]

Short leukocyte telomere length ( LTL) is associated with atherosclerosis in adults and diminished survival in the elderly. LTL dynamics are defined by LTL at birth, which is highly variable, and its age-dependent attrition thereafter, which is rapid during the first 20 years of life. We examined whether age-dependent LTL attrition during adulthood can substantially affect individuals' LTL ranking (e.g., longer or shorter LTL) in relation to their peers. We measured LTL in samples donated 12 years apart on average by 1156 participants in four longitudinal studies. We observed correlations of 0.91-0.96 between baseline and follow-up LTLs. Ranking individuals by deciles revealed that 94.1% (95% confidence interval of 92.6-95.4%) showed no rank change or a 1 decile change over time. We conclude that in adults, LTL is virtually anchored to a given rank with the passage of time. Accordingly, the links of LTL with atherosclerosis and longevity appear to be established early in life. It is unlikely that lifestyle and its modification during adulthood exert a major impact on LTL ranking. [ABSTRACT FROM AUTHOR]

Genetic interactions or epistasis could make a substantial contribution to variation in human complex traits including longevity. However, detecting epistatic interactions in high dimensional datasets is difficult due to various reasons including multiple testing of correlated tests. We introduce a novel permutation strategy to the case-only analysis of gene-by-gene interaction using multiple SNPs. The method is applied to genes coding for Forkhead box O transcription factors which recently have been associated with human longevity across different populations hypothesizing that epistatic interaction in the regulation and expression of the FOXO gene family could contribute to the human longevity phenotype. Genotype data were collected from 1088 individuals from the Danish 1905 birth cohort aged over 92-93 years with 12 SNPs in the FOXO1a and 15 SNPs in the FOXO3a genes. Our analysis detected a joint effect between rs9486902 in FOXO3a and rs2701858 in FOXO1a that highly significantly contributes to human longevity ( OR = 3.23, 95% CI: 2.93-3.53) which is consistent in both males and females. Our results were compared with published studies, and importance of our novel method and findings was discussed. [ABSTRACT FROM AUTHOR]

Accumulation of DNA damage deriving from exogenous and endogenous sources has significant consequences for cellular survival, and is implicated in aging, cancer, and neurological diseases. Different DNA repair pathways have evolved in order to maintain genomic stability. Genetic and environmental factors are likely to influence DNA repair capacity. In order to gain more insight into the genetic and environmental contribution to the molecular basis of DNA repair, we have performed a human twin study, where we focused on the consequences of some of the most abundant types of DNA damage (single-strand breaks), and some of the most hazardous lesions (DNA double-strand breaks). DNA damage signaling response (Gamma-H2AX signaling), relative amount of endogenous damage, and DNA-strand break repair capacities were studied in peripheral blood mononuclear cells from 198 twins (94 monozygotic and 104 dizygotic). We did not detect genetic effects on the DNA-strand break variables in our study. Environ. Mol. Mutagen. 54:414-420, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Exogenous and endogenous damage to DNA is constantly challenging the stability of our genome. This DNA damage increase the frequency of errors in DNA replication, thus causing point mutations or chromosomal rearrangements and has been implicated in aging, cancer, and neurodegenerative diseases. Therefore, efficient DNA repair is vital for the maintenance of genome stability. The general notion has been that DNA repair capacity decreases with age although there are conflicting results. Here, we focused on potential age-associated changes in DNA damage response and the capacities of repairing DNA single-strand breaks ( SSBs) and double-strand breaks ( DSBs) in human peripheral blood mononuclear cells ( PBMCs). Of these lesions, DSBs are the least frequent but the most dangerous for cells. We have measured the level of endogenous SSBs, SSB repair capacity, γ-H2AX response, and DSB repair capacity in a study population consisting of 216 individuals from a population-based sample of twins aged 40-77 years. Age in this range did not seem to have any effect on the SSB parameters. However, γ-H2AX response and DSB repair capacity decreased with increasing age, although the associations did not reach statistical significance after adjustment for batch effect across multiple experiments. No gender differences were observed for any of the parameters analyzed. Our findings suggest that in PBMCs, the repair of SSBs is maintained until old age, whereas the response to and the repair of DSBs decrease. [ABSTRACT FROM AUTHOR]

The accumulation of epigenetic changes was proposed to contribute to the age-related increase in the risk of most common diseases. In this study on 230 monozygotic twin pairs (MZ pairs), aged 18-89 years, we investigated the occurrence of epigenetic changes over the adult lifespan. Using mass spectrometry, we investigated variation in global (LINE1) DNA methylation and in DNA methylation at INS, KCNQ1OT1, IGF2, GNASAS, ABCA1, LEP, and CRH, candidate loci for common diseases. Except for KCNQ1OT1, interindividual variation in locus-specific DNA methylation was larger in old individuals than in young individuals, ranging from 1.2-fold larger at ABCA1 ( P = 0.010) to 1.6-fold larger at INS ( P = 3.7 × 10−07). Similarly, there was more within-MZ-pair discordance in old as compared with young MZ pairs, except for GNASAS, ranging from an 8% increase in discordance each decade at CRH ( P = 8.9 × 10−06) to a 16% increase each decade at LEP ( P = 2.0 × 10−08). Still, old MZ pairs with strikingly similar DNA methylation were also observed at these loci. After 10-year follow-up in elderly twins, the variation in DNA methylation showed a similar pattern of change as observed cross-sectionally. The age-related increase in methylation variation was generally attributable to unique environmental factors, except for CRH, for which familial factors may play a more important role. In conclusion, sustained epigenetic differences arise from early adulthood to old age and contribute to an increasing discordance of MZ twins during aging. [ABSTRACT FROM AUTHOR]

Aim: Studies carried out in Western populations have shown age-related changes in multiple health domains together with gender-specific patterns. By focusing on five health domains, self-rated health, hand grip strength, sit-to-stand test, cognitive performance and depression, we examined the age trajectories in general health in a cross-sectional Chinese sample representing the world's largest ethnic population and compare with Danish data that represent Western populations in developed countries. Methods: Multiple regression models were fitted to compare patterns across genders and populations together with gender- and population-specific patterns in age-related decline. Results: Better self-rated health for males than for females was observed in both countries, and Danes reported better health than the Chinese for both genders. For hand grip strength, significant gender differences were shown across countries and significant population differences observed in Danish and Chinese males. There was no population difference in sit-to-stand time across genders. Female Danes outperformed males in cognitive performance. No significant gender differences in depression were observed in both populations. Conclusion: Our cross population analysis identified significant gender and population differences suggesting endogenous biological, physical and social environmental determinants in age-related decline in general health. Geriatr Gerontol Int 2012; 12: 431-439. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the prevalence and associated health factors of indoor mobility-related fatigability in nonagenarians. Design A cross-sectional observational study of all Danes born in 1905 and assessed in 1998. Setting Community, sheltered housing and nursing homes. Participants Individuals aged 92 and 93 ( N = 1,181) who were independent of help in basic indoor mobility. Measurements Fatigability in basic indoor mobility was defined as a subjective feeling of fatigue when transferring or walking indoors. Other standardized assessments include self-report measures of medical history and performance-based assessments of walking speed and maximum handgrip strength. Results Twenty-six percent of participants reported fatigability when transferring or walking indoors; fatigability was more common in participants living in sheltered housing (32%) than in those living independently (23%, P < .001). Cardiovascular diseases, musculoskeletal pain, medications, walking speed, and depressive symptoms were independently associated with fatigability. Conclusion Fatigability in basic everyday mobility is common in nondisabled nonagenarians. The results also indicate important associations between fatigability and potentially modifiable health factors. [ABSTRACT FROM AUTHOR]

Summary Telomerase is of key importance for telomere maintenance, and variants of the genes encoding its major subunits, telomerase reverse transcriptase ( TERT) and telomerase RNA component ( TERC), are candidates for interindividual variation in telomere length. Recently, the two SNPs rs3772190 and rs12696304 in the TERC locus were reported to be associated with leukocyte telomere length (LTL) in two genome-wide association studies, while one haplotype of TERT (rs2853669, rs2736098, rs33954691, and rs2853691) has been reported to be associated with both LTL and longevity in a candidate gene study. In this study, we investigated the two TERC and four TERT SNPs in middle-aged, old, and oldest-old Danes (58-100 years) and their association with LTL ( n = 864) and longevity ( n = 1069). Furthermore, data on 11 TERT tagging SNPs in 1089 oldest-old and 736 middle-aged Danes were investigated with respect to longevity. For all SNPs, the association with longevity was investigated using both a cross-sectional and a longitudinal approach. Applying an additive model, we found association of LTL with the minor TERC alleles of rs3772190 (A) and rs12696304 (G), such that a shorter LTL was seen in rs3772190 A carriers (regression coefficient = −0.08, P = 0.011) and in male rs12696304 G carriers (regression coefficient = −0.13, P = 0.014). No TERT variations showed association. Moreover, the A allele of rs3772190 ( TERC) was found to be associated with longevity [hazard rate (AG + AA) = 1.31, P = 0.006]. No associations with longevity were observed for the TERT SNPs or haplotypes. Our study, thus, indicates that TERC is associated with both LTL and longevity in humans. [ABSTRACT FROM AUTHOR]

The genetic loci affecting the commonly used BMI have been intensively investigated using linkage approaches in multiple populations. This study aims at performing the first genome-wide linkage scan on BMI in the Chinese population in mainland China with hypothesis that heterogeneity in genetic linkage could exist in different ethnic populations. BMI was measured from 126 dizygotic twins in Qingdao municipality who were genotyped using high-resolution Affymetrix Genome-Wide Human SNP arrays containing about 1 million single-nucleotide polymorphisms (SNPs). Nonparametric linkage analysis was performed with Merlin software package for linkage analysis using variance components approach for quantitative trait loci mapping. We identified a strong linkage peak at the end of chromosome 7 (7q36 at 186 cM) with a lod score of 4.06 which overlaps with that reported by a large multicenter study in western countries. Multiple loci showing suggestive linkage were found on chromosome 1 (lod score 2.38 at 242 cM), chromosome 8 (2.48 at 95 cM), and chromosome 14 (2.2 at 89.4 cM). The strong linkage identified in the Chinese subjects that is consistent with that found in populations of European origin could suggest the existence of evolutionarily preserved genetic mechanisms for BMI whereas the multiple suggestive loci could represent genetic effect from gene-environment interaction as a result of population-specific environmental adaptation. [ABSTRACT FROM AUTHOR]

We performed a genome wide association analysis of maternally-mediated genetic effects and parent-of-origin (POO) effects on risk of orofacial clefting (OC) using over 2,000 case-parent triads collected through an international cleft consortium. We used log-linear regression models to test individual SNPs. For SNPs with a P-value <10−5 for maternal genotypic effects, we also applied a haplotype-based method, TRIMM, to extract potential information from clusters of correlated SNPs. None of the SNPs were significant at the genome wide level. Our results suggest neither maternal genome nor POO effects play major roles in the etiology of OC in our sample. This finding is consistent with previous genetic studies and recent population-based cohort studies in Norway and Denmark, which showed no apparent difference between mother-to-offspring and father-to-offspring recurrence of clefting. We, however, cannot completely rule out maternal genome or POO effects as risk factors because very small effects might not be detectable with our sample size, they may influence risk through interactions with environmental exposures or may act through a more complex network of interacting genes. Thus, the most promising SNPs identified by this study may still be worth further investigation. Published 2012. This article is a U.S. Government work and is in the public domain in the USA. [ABSTRACT FROM AUTHOR]