Publications by authors named "Lene Christiansen"

146 Publications

Global Gene Expression Profiling and Transcription Factor Network Analysis of Cognitive Aging in Monozygotic Twins.

Front Genet 2021 14;12:675587. Epub 2021 Jun 14.

Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark.

Cognitive aging is one of the major problems worldwide, especially as people get older. This study aimed to perform global gene expression profiling of cognitive function to identify associated genes and pathways and a novel transcriptional regulatory network analysis to identify important regulons. We performed single transcript analysis on 400 monozygotic twins using an assumption-free generalized correlation coefficient (GCC), linear mixed-effect model (LME) and kinship model and identified six probes (one significant at the standard FDR < 0.05 while the other results were suggestive with 0.18 ≤ FDR ≤ 0.28). We combined the GCC and linear model results to cover diverse patterns of relationships, and meaningful and novel genes like , and were detected. Our exploratory study showed the downregulation of all these genes with increasing cognitive function or vice versa except the gene, which was upregulated with increasing cognitive function. Linear models found only and , the other genes were captured by GCC. Significant functional pathways (FDR < 3.95e-10) such as focal adhesion, ribosome, cysteine and methionine metabolism, Huntington's disease, eukaryotic translation elongation, nervous system development, influenza infection, metabolism of RNA, and cell cycle were identified. A total of five regulons (FDR< 1.3e-4) were enriched in a transcriptional regulatory analysis in which and were activated and , and were repressed regulons. The genome-wide transcription analysis using both assumption-free GCC and linear models identified important genes and biological pathways implicated in cognitive performance, cognitive aging, and neurological diseases. Also, the regulatory network analysis revealed significant activated and repressed regulons on cognitive function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2021.675587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236849PMC
June 2021

Differential lncRNA expression profiling of cognitive function in middle and old aged monozygotic twins using generalized association analysis.

J Psychiatr Res 2021 Aug 2;140:197-204. Epub 2021 Jun 2.

Unit of Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Denmark; Unit of Human Genetics, Department of Clinical Research, University of Southern Denmark, Denmark. Electronic address:

Cognitive impairment is the most prominent symptom in neurodegenerative disorders affecting quality of life and mortality. However, despite years of research, the molecular mechanism underlying the regulation of cognitive function and its impairment is poorly understood. This study aims to elucidate the role of long non-coding RNAs (lncRNAs) expression and lncRNA-mRNA interaction networks, by analyzing lncRNA expression in whole blood samples of 400 middle and old aged monozygotic twins in association with cognitive function using both linear models and a generalized correlation coefficient (GCC) to capture the diverse patterns of correlation. We detected 13 probes (p < 1e-03) displaying nonlinear and 7 probes (p < 1e-03) showing linear correlations. After combining the results, we identified 20 lncRNA probes with p < 1e-03. The top lncRNA probes were annotated to genes, along with the non-coding MALAT1, that play roles in neurodegenerative diseases. The top lncRNAs were linked to functional clusters including peptidyl-glycine modification, vascular smooth muscle cells, mitotic spindle organization and protein tyrosine phosphatase. In addition, mapping of the top significant lncRNAs to the lncRNA-mRNA interaction network detected significantly enriched biological pathways involving neuroactive ligand-receptor interaction, proteasome and chemokines. We show that GCC served as a complementary approach in detecting lncRNAs missed by the conventional linear models. A combination of GCC and linear models identified lncRNAs of diverse patterns of association enriched for GO biological and molecular functions meaningful in cognitive performance and cognitive decline. The novel lncRNA regulatory network further contributed to detect significant pathways implicated in cognition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpsychires.2021.05.074DOI Listing
August 2021

Genetic Meta-Analysis of Twin Birth Weight Shows High Genetic Correlation with Singleton Birth Weight.

Hum Mol Genet 2021 May 6. Epub 2021 May 6.

Department of Medical Epidemiology and Biostatististics, Karolinska Institutet, Stockholm, Sweden.

Birth weight (BW) is an important predictor of newborn survival and health and has associations with many adult health outcomes, including cardio-metabolic disorders, autoimmune diseases, and mental health. On average, twins have a lower BW than singletons as a result of a different pattern of fetal growth and shorter gestational duration. Therefore, investigations into the genetics of BW often exclude data from twins, leading to a reduction in sample size and remaining ambiguities concerning the genetic contribution to BW in twins. In this study, we carried out a genome-wide association meta-analysis of BW in 42 212 twin individuals and found a positive correlation of beta values (Pearson's r = 0.66, 95% confidence interval [CI]: 0.47-0.77) with 150 previously reported genome-wide significant variants for singleton BW. We identified strong positive genetic correlations between BW in twins and numerous anthropometric traits, most notably with BW in singletons (genetic correlation [rg] = 0.92, 95% CI: 0.66-1.18). Genetic correlations of BW in twins with a series of health-related traits closely resembled those previously observed for BW in singletons. Polygenic scores constructed from a genome-wide association study on BW in UK Biobank demonstrated strong predictive power in a target sample of Dutch twins and singletons. Together, our results indicate that a similar genetic architecture underlies BW in twins and singletons and that future genome-wide studies might benefit from including data from large twin registers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddab121DOI Listing
May 2021

Genome-wide association analysis of cognitive function in Danish long-lived individuals.

Mech Ageing Dev 2021 04 16;195:111463. Epub 2021 Feb 16.

The Danish Twin Registry and The Danish Aging Research Center, Department of Public Health, University of Southern Denmark, J.B. Winsloews Vej 9B, 5000 Odense C, Denmark; Department of Clinical Genetics, Odense University Hospital, J.B. Winsloews Vej 4, 5000 Odense C, Denmark.

Cognitive function is a substantially heritable trait related to numerous important life outcomes. Several genome-wide association studies of cognitive function have in recent years led to the identification of thousands of significantly associated loci and genes. Individuals included in these studies have rarely been nonagenarians and centenarians, and since cognitive function is an important component of quality of life for this rapidly expanding demographic group, there is a need to explore genetic factors associated with individual differences in cognitive function at advanced ages. In this study, we pursued this by performing a genome-wide association study of cognitive function in 490 long-lived Danes (age range 90.1-100.8 years). While no genome-wide significant SNPs were identified, suggestively significant SNPs (P < 1 × 10) were mapped to several interesting genes, including ZWINT, CELF2, and DNAH5, and the glutamate receptor genes GRID2 and GRM7. Additionally, results from a gene set over-representation analysis indicated potential roles of gene sets related to G protein-coupled receptor (GPCR) signaling, interaction between L1 and ankyrins, mitogen-activated protein kinase (MAPK) signaling, RNA degradation, and cell cycle. Larger studies are needed to shed further light on the possible importance of these suggestive genes and pathways in cognitive function in nonagenarians and centenarians.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mad.2021.111463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035220PMC
April 2021

Novel DNA methylation marker discovery by assumption-free genome-wide association analysis of cognitive function in twins.

Aging Cell 2021 02 2;20(2):e13293. Epub 2021 Feb 2.

Unit of Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/acel.13293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884045PMC
February 2021

Exome-Wide Association Study Identifies FN3KRP and PGP as New Candidate Longevity Genes.

J Gerontol A Biol Sci Med Sci 2021 Apr;76(5):786-795

Institute of Clinical Molecular Biology, Kiel University, University Hospital Schleswig-Holstein, Germany.

Despite enormous research efforts, the genetic component of longevity has remained largely elusive. The investigation of common variants, mainly located in intronic or regulatory regions, has yielded only little new information on the heritability of the phenotype. Here, we performed a chip-based exome-wide association study investigating 62 488 common and rare coding variants in 1248 German long-lived individuals, including 599 centenarians and 6941 younger controls (age < 60 years). In a single-variant analysis, we observed an exome-wide significant association between rs1046896 in the gene fructosamine-3-kinase-related-protein (FN3KRP) and longevity. Noteworthy, we found the longevity allele C of rs1046896 to be associated with an increased FN3KRP expression in whole blood; a database look-up confirmed this effect for various other human tissues. A gene-based analysis, in which potential cumulative effects of common and rare variants were considered, yielded the gene phosphoglycolate phosphatase (PGP) as another potential longevity gene, though no single variant in PGP reached the discovery p-value (1 × 10E-04). Furthermore, we validated the previously reported longevity locus cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1). Replication of our results in a French longevity cohort was only successful for rs1063192 in CDKN2B-AS1. In conclusion, we identified 2 new potential candidate longevity genes, FN3KRP and PGP which may influence the phenotype through their role in metabolic processes, that is, the reverse glycation of proteins (FN3KRP) and the control of glycerol-3-phosphate levels (PGP).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/gerona/glab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087267PMC
April 2021

Generalized correlation coefficient for genome-wide association analysis of cognitive ability in twins.

Aging (Albany NY) 2020 11 24;12(22):22457-22494. Epub 2020 Nov 24.

Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark.

Despite a strong genetic background in cognitive function only a limited number of single nucleotide polymorphisms (SNPs) have been found in genome-wide association studies (GWASs). We hypothesize that this is partially due to mis-specified modeling concerning phenotype distribution as well as the relationship between SNP dosage and the level of the phenotype. To overcome these issues, we introduced an assumption-free method based on generalized correlation coefficient (GCC) in a GWAS of cognitive function in Danish and Chinese twins to compare its performance with traditional linear models. The GCC-based GWAS identified two significant SNPs in Danish samples (rs71419535, p 1.47e-08; rs905838, p = 1.69e-08) and two significant SNPs in Chinese samples (rs2292999, p = 9.27e-10; rs17019635, p = 2.50e-09). In contrast, linear models failed to detect any genome-wide significant SNPs. The number of top significant genes overlapping between the two samples in the GCC-based GWAS was higher than when applying linear models. The GCC model identified significant genetic variants missed by conventional linear models, with more replicated genes and biological pathways related to cognitive function. Moreover, the GCC-based GWAS was robust in handling correlated samples like twin pairs. GCC is a useful statistical method for GWAS that complements traditional linear models for capturing genetic effects beyond the additive assumption.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.104198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746382PMC
November 2020

Differential long noncoding RNA profiling of BMI in twins.

Epigenomics 2020 09 9;12(17):1531-1541. Epub 2020 Sep 9.

Unit of Epidemiology, Biostatistics & Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark.

Many efforts have been deployed to identify genetic variants associated with BMI. Alternatively, we explore epigenetic contribution to BMI variation by focusing on long noncoding RNAs (lncRNAs) which represents a key layer of epigenetic control. We analyzed lncRNA expression in whole blood of 229 monozygotic twin pairs in association with BMI using generalized estimating equations. Six lncRNA probes were identified as significant (false discovery rate <0.05), with BMI showing causal effects on the expression of the significant lncRNAs. Functional annotation of differential profiles identified Gene ontology biological processes including kidney development, regulations of lipid biosynthetic process, circadian rhythm, notch signaling, etc. Whole blood lncRNAs are significantly expressed in response to BMI variation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/epi-2020-0033DOI Listing
September 2020

A decade of epigenetic change in aging twins: Genetic and environmental contributions to longitudinal DNA methylation.

Aging Cell 2020 08 24;19(8):e13197. Epub 2020 Jul 24.

Karolinska Institutet, Stockholm, Sweden.

Background: Epigenetic changes may result from the interplay of environmental exposures and genetic influences and contribute to differences in age-related disease, disability, and mortality risk. However, the etiologies contributing to stability and change in DNA methylation have rarely been examined longitudinally.

Methods: We considered DNA methylation in whole blood leukocyte DNA across a 10-year span in two samples of same-sex aging twins: (a) Swedish Adoption Twin Study of Aging (SATSA; N = 53 pairs, 53% female; 62.9 and 72.5 years, SD = 7.2 years); (b) Longitudinal Study of Aging Danish Twins (LSADT; N = 43 pairs, 72% female, 76.2 and 86.1 years, SD=1.8 years). Joint biometrical analyses were conducted on 358,836 methylation probes in common. Bivariate twin models were fitted, adjusting for age, sex, and country.

Results: Overall, results suggest genetic contributions to DNA methylation across 358,836 sites tended to be small and lessen across 10 years (broad heritability M = 23.8% and 18.0%) but contributed to stability across time while person-specific factors explained emergent influences across the decade. Aging-specific sites identified from prior EWAS and methylation age clocks were more heritable than background sites. The 5037 sites that showed the greatest heritable/familial-environmental influences (p < 1E-07) were enriched for immune and inflammation pathways while 2020 low stability sites showed enrichment in stress-related pathways.

Conclusions: Across time, stability in methylation is primarily due to genetic contributions, while novel experiences and exposures contribute to methylation differences. Elevated genetic contributions at age-related methylation sites suggest that adaptions to aging and senescence may be differentially impacted by genetic background.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/acel.13197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431820PMC
August 2020

A Genome-Wide Integrative Association Study of DNA Methylation and Gene Expression Data and Later Life Cognitive Functioning in Monozygotic Twins.

Front Neurosci 2020 9;14:233. Epub 2020 Apr 9.

Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark.

Monozygotic twins are genetically identical but rarely phenotypically identical. Epigenetic and transcriptional variation could influence this phenotypic discordance. Investigation of intra-pair differences in molecular markers and a given phenotype in monozygotic twins controls most of the genetic contribution, enabling studies of the molecular features of the phenotype. This study aimed to identify genes associated with cognition in later life using integrated enrichment analyses of the results of blood-derived intra-pair epigenome-wide and transcriptome-wide association analyses of cognition in 452 middle-aged and old-aged monozygotic twins (56-80 years). Integrated analyses were performed with an unsupervised approach using KeyPathwayMiner, and a supervised approach using the KEGG and Reactome databases. The supervised approach identified several enriched gene sets, including "neuroactive ligand receptor interaction" (-value = 1.6210-2), "Neurotrophin signaling" (-value = 2.5210-3), "Alzheimer's disease" (-value = 1.2010-2), and "long-term depression" (-value = 1.6210-2). The unsupervised approach resulted in a 238 gene network, including the Alzheimer's disease gene (Amyloid Beta Precursor Protein) as an exception node, and several novel candidate genes. The strength of the unsupervised method is that it can reveal previously uncharacterized sub-pathways and detect interplay between biological processes, which remain undetected by the current supervised methods. In conclusion, this study identified several previously reported cognition genes and pathways and, additionally, puts forward novel candidates for further verification and validation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnins.2020.00233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160301PMC
April 2020

Cohort Differences in the Associations of Selected Candidate Genes With Risk of All-Cause Mortality at Advanced Ages.

Am J Epidemiol 2020 07;189(7):708-716

Considerable efforts have been made to identify the genetic basis of human longevity, with only limited progress. One important drawback of current genetic studies is the limited knowledge of gene-environment interaction. Using 2 cohorts of long-lived individuals born in 1905 and 1915 in Denmark, we performed survival analysis to estimate risk of mortality for major candidate genes of aging and longevity and their cohort effects. Through statistical modeling that combines individual genetic and survival information with cohort-specific survival data, we estimated the relative risks of mortality from ages 95 to 103 years associated with genetic variants in apolipoprotein E (APOE), forkhead box class O3a, clusterin, and phosphatidylinositol binding clathrin assembly protein. Our analysis estimated a decreased risk of carrying the APOE$\varepsilon $4 allele (change in risk = -0.403, 95% confidence interval (CI): -0.831, 0.021; P = 0.040) in men of the later cohort, although the allele itself was harmful to survival across sexes (relative risk = 1.161, 95% CI: 1.027, 1.345; P = 0.026). We also estimated a cohort effect of increased risk for the minor allele of rs3851179 in phosphatidylinositol binding clathrin assembly protein with borderline significance (change in risk = 0.165, 95% CI: -0.010, 0.331; P = 0.052) in women. Our estimated significant cohort effect on APOE$\varepsilon $4 is indicative of the interplay between the gene and the changing environment that modulates survival at extreme ages.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/aje/kwaa007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393313PMC
July 2020

Inspiratory muscle strength and walking capacity in patients with COPD.

Eur Clin Respir J 2020 9;7(1):1700086. Epub 2019 Dec 9.

Department of Clinical Research, Copenhagen University Hospital, Nordsjælland, Denmark.

: It has been suggested that patients with inspiratory muscle weakness could benefit from specific inspiratory muscle training (IMT). We aimed to examine the frequency of patients with inspiratory muscle weakness in a Danish hospital-based outpatient pulmonary rehabilitation program, and to evaluate the association between inspiratory muscle strength and peripheral muscle strength and walking capacity. : Maximal Inspiratory Pressure (MIP) was assessed in 97 patients with COPD (39 men, 58 women, mean age years 70 ± 9, forced expiratory volume in 1 s ((FEV) = 35 ± 10% pred.). The impact of MIP on knee-extension strength, walking distance, and symptom burden was evaluated using multiple linear regression analyses. : The MIP of the patients with COPD was 63 (95% CI 59; 67) cmHO and it was significantly reduced compared to gender and age-matched reference values 76 (95% CI 73; 79) cmHO (p < 0.001). Seven patients (7.2%) were under the lower limit of normal. MIP was negatively correlated with increasing age, female gender, decreasing knee-extension strength and lower FEV% pred. Walking distance was associated with knee-extension strength and it was not associated with MIP. : Maximal inspiratory pressure was reduced in patients with COPD but only a few patients had a weak MIP. Whilst MIP was associated with leg muscle strength, it was not associated with walking distance or symptoms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/20018525.2019.1700086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913623PMC
December 2019

Global expression profiling of cognitive level and decline in middle-aged monozygotic twins.

Neurobiol Aging 2019 12 26;84:141-147. Epub 2019 Aug 26.

The Danish Twin Registry and The Danish Aging Research Center, Department of Public Health, University of Southern Denmark, Odense C, Denmark; Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen OE, Denmark.

Only few studies have investigated the genomewide transcriptome of normative cognitive aging. We therefore aimed at investigating blood gene expression patterns associated with cognitive aging using a population-based sample of 235 middle-aged monozygotic twin pairs with longitudinal data on cognitive function. This unique setup enabled examination of gene expression differences associated with individual and intrapair differences in cognitive level and change while controlling for underlying genetic variation and shared early environment. Overall, increased expression of several gene sets was found to strongly correlate with a lower cognitive level and cognitive decline. The most significantly correlated gene sets were related to protein metabolism, translation, RNA metabolism, infectious disease, and the immune system, which are all processes previously linked to transcription signatures of pathological and normal brain aging, and aging in blood. The results of our study thus suggest that gene expression patterns of cognitive level and decline in our sample mirror those seen in cognitively impaired individuals, which could point toward a more generic response to cognitive aging and aging in general.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2019.08.019DOI Listing
December 2019

A meta-analysis of genome-wide association studies identifies multiple longevity genes.

Nat Commun 2019 08 14;10(1):3669. Epub 2019 Aug 14.

Department of Public Health, University of Southern Denmark, 5000, Odense C, Denmark.

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-11558-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694136PMC
August 2019

Epigenome-wide exploratory study of monozygotic twins suggests differentially methylated regions to associate with hand grip strength.

Biogerontology 2019 10 28;20(5):627-647. Epub 2019 Jun 28.

Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, J.B. Winsløws Vej 9B, 5000, Odense C, Denmark.

Hand grip strength is a measure of muscular strength and is used to study age-related loss of physical capacity. In order to explore the biological mechanisms that influence hand grip strength variation, an epigenome-wide association study (EWAS) of hand grip strength in 672 middle-aged and elderly monozygotic twins (age 55-90 years) was performed, using both individual and twin pair level analyses, the latter controlling the influence of genetic variation. Moreover, as measurements of hand grip strength performed over 8 years were available in the elderly twins (age 73-90 at intake), a longitudinal EWAS was conducted for this subsample. No genome-wide significant CpG sites or pathways were found, however two of the suggestive top CpG sites were mapped to the COL6A1 and CACNA1B genes, known to be related to muscular dysfunction. By investigating genomic regions using the comb-p algorithm, several differentially methylated regions in regulatory domains were identified as significantly associated to hand grip strength, and pathway analyses of these regions revealed significant pathways related to the immune system, autoimmune disorders, including diabetes type 1 and viral myocarditis, as well as negative regulation of cell differentiation. The genes contributing to the immunological pathways were HLA-B, HLA-C, HLA-DMA, HLA-DPB1, MYH10, ERAP1 and IRF8, while the genes implicated in the negative regulation of cell differentiation were IRF8, CEBPD, ID2 and BRCA1. In conclusion, this exploratory study suggests hand grip strength to associate with differentially methylated regions enriched in immunological and cell differentiation pathways, and hence merits further investigations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10522-019-09818-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733812PMC
October 2019

DNA methylome profiling in identical twin pairs discordant for body mass index.

Int J Obes (Lond) 2019 12 31;43(12):2491-2499. Epub 2019 May 31.

Epidemiology and Biostatistics, Department of Public Health, University of Southern Denmark, Odense, Denmark.

Objective: Body mass index (BMI) serves as an important measurement of obesity and adiposity, which are highly correlated with cardiometabolic diseases. Although high heritability has been estimated, the identified genetic variants by genetic association studies only explain a small proportion of BMI variation. As an active effort for further exploring the molecular basis of BMI variation, large-scale epigenome-wide association studies have been conducted but with limited number of loci reported, perhaps due to poorly controlled confounding factors, including genetic factors. Being genetically identical, monozygotic twins discordant for BMI are ideal subjects for analyzing the epigenetic association between DNA methylation and BMI, providing perfect control on their genetic makeups largely responsible for BMI variation.

Subjects: We performed an epigenome-wide association study on BMI using 30 identical twin pairs (15 male and 15 female pairs) with age ranging from 39 to 72 years and degree of BMI discordance ranging from 3-7.5 kg/m. Methylation data from whole blood samples were collected using the reduced representation bisulfite sequencing technique.

Results: After adjusting for blood cell composition and clinical variables, we identified 136 CpGs with p-value < 1e-4, 30 CpGs with p < 1e-05 but no CpGs reached genome-wide significance. Genomic region-based analysis found 11 differentially methylated regions harboring coding and non-coding genes some of which were validated by gene expression analysis on independent samples.

Conclusions: Our DNA methylation sequencing analysis on identical twins provides new references for the epigenetic regulation on BMI and obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41366-019-0382-4DOI Listing
December 2019

Advanced Parental Age at Conception and Sex Affects Mitochondrial DNA Copy Number in Human and Fruit Flies.

J Gerontol A Biol Sci Med Sci 2019 11;74(12):1853-1860

The Danish Aging Research Center and The Danish Twin Registry, Epidemiology and Biostatistics Unit, Institute of Public Health, University of Southern Denmark, Odense.

Aging is a multifactorial trait caused by early as well as late-life circumstances. A society trend that parents deliberately delay having children is of concern to health professionals, for example as advanced parental age at conception increases disease risk profiles in offspring. We here aim to study if advanced parental age at conception affects mitochondrial DNA content, a cross-species biomarker of general health, in adult human twin offspring and in a model organism. We find no deteriorated mitochondrial DNA content at advanced parental age at conception, but human mitochondrial DNA content was higher in females than males, and the difference was twofold higher at advanced maternal age at conception. Similar parental age effects and sex-specific differences in mitochondrial DNA content were found in Drosophila melanogaster. In addition, parental longevity in humans associates with both mitochondrial DNA content and parental age at conception; thus, we carefully propose that a poorer disease risk profile from advanced parental age at conception might be surpassed by superior effects of parental successful late-life reproduction that associate with parental longevity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/gerona/glz070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357451PMC
November 2019

DNA methylome profiling of all-cause mortality in comparison with age-associated methylation patterns.

Clin Epigenetics 2019 02 8;11(1):23. Epub 2019 Feb 8.

Epidemiology and Biostatistics, Department of Public Health, Faculty of Health Science, University of Southern Denmark, J. B. Winsløws Vej 9B, DK-5000, Odense, Denmark.

Background: Multiple epigenome-wide association studies have been performed to identify DNA methylation patterns regulated by aging or correlated with risk of death. However, the inter-relatedness of the epigenetic basis of aging and mortality has not been well investigated.

Methods: Using genome-wide DNA methylation data from the Lothian Birth Cohorts, we conducted a genome-wide association analysis of all-cause mortality and compared this with age-associated methylation patterns reported on the same samples.

Results: Survival analysis using the Cox regression model identified 2552 CpG sites with genome-wide significance (false discovery rate < 0.05) for all-cause mortality. CpGs whose methylation levels are associated with increased mortality appear more distributed from the gene body to the intergenic regions whereas CpGs whose methylation levels are associated with decreased mortality is more concentrated at the promoter regions. In comparison with reported CpGs displaying significant age-dependent methylation patterns in the same samples, we observed a limited but highly significant overlap between mortality-associated and age-associated CpGs (p value 2.52e-06). Most importantly, the overlapping CpGs are dominated by those whose overall age-related methylation patterns reduce the risk of death.

Conclusion: All-cause mortality is significantly associated with altered methylation at multiple genomic sites with differential distribution in gene regions for CpGs correlated with increased or decreased risk of death. The age-dependent methylation changes could reflect an active response to the aging process that contributes to maintain individual survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-019-0622-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368749PMC
February 2019

Longitudinal changes in the genetic and environmental influences on the epigenetic clocks across old age: Evidence from two twin cohorts.

EBioMedicine 2019 Feb 28;40:710-716. Epub 2019 Jan 28.

Department of Psychology, The University of California at Riverside, California, USA.

Background: Measures based on DNA methylation, epigenetic clocks, have recently gained attraction as predictors of mortality and age-related pathologies. However, the origins of variation in these measures are not well understood.

Methods: In a pooled sample of 104 Swedish and Danish twin pairs, we estimated, at the mean age of 70 (baseline) and 79 years (follow-up), the genetic and environmental influences on the Horvath and Levine clocks.

Findings: A model incorporating additive genetic (A) and person-specific environmental (E) influences best explained the variation in both clocks. Heritability was estimated at 55% at baseline and at 51% at follow-up for the Horvath clock and 34% at baseline and 41% at follow-up for the Levine clock. For the Horvath clock, new sources of A influences emerged at follow-up, whereas for the Levine clock, the same A influences accounted for the genetic variance at both measurement occasions. The cross-time phenotypic correlations, 0·52 for the Horvath clock and 0·36 for the Levine clock, were mediated primarily by genetic factors, whereas the person-specific environmental factors were completely different at the two measurement occasions.

Interpretation: For both clocks, new sources of person-specific environmental influences emerge with age. The epigenetic clocks might thus be responsive to new environmental stimuli even at old age. FUND: NIH (R01;AG04563;AG10175;AG028555) the MacArthur Foundation Research Network on Successful Aging, FAS/FORTE (97:0147:1B;2009-0795), Swedish Research Council (825-2007-7460;825-2009-6141;521-2013-8689;2015-03255;2015-06796;2018-02077), FORTE (2013-2292), the Strategic Research Program in Epidemiology at KI, VELUX FOUNDATION, NIA (P01-AG08761), the EU (FP7/2007-2011;259679) and The Danish National Program for Research Infrastructure 2007 (9-063256).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2019.01.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413471PMC
February 2019

White blood cell mitochondrial DNA copy number is decreased in rheumatoid arthritis and linked with risk factors. A twin study.

J Autoimmun 2019 01 14;96:142-146. Epub 2018 Oct 14.

Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark; Unit of Human Genetics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark. Electronic address:

Low mitochondrial DNA copy number (mtDNA CN) has been associated with e.g. cancer, cardiovascular and autoimmune diseases. We aimed to study a potential association between mtDNA CN and rheumatoid arthritis (RA). The relative quantity of mitochondrial DNA compared to nuclear DNA was measured in peripheral white blood cells from 149 RA affected twin pairs and 1321 non-affected twin pairs. Multiple regression analysis including RA discordant twin pairs was performed in order to separate specific effects of RA and familial RA predisposition using non-RA affected twin pairs as reference group. In addition, we performed a twin pair level analysis including only RA discordant twin pairs evaluating the effect of cell type, auto antibodies and RA genetic risk factors. Both the RA twins and their non-affected co-twins had significantly lower mtDNA CN than non-affected twins (-28.7 and -23.1 mtDNA CN, respectively). Adjusting for cell count attenuated these differences (-23.1 mtDNA CN and -20.1 mtDNA CN respectively). Within RA discordant twin pairs PTPN22(T) positive RA twins had a significantly lower amount than their co-twins (-16.3 mtDNA CN). PTPN22(T) had no effect among twins from non-affected twin pairs. MtDNA CN is significantly lower in persons with established RA and in predisposed non-affected RA co-twins suggesting that mitochondrial variation may be involved in the RA disease pathways. Our results also suggest that the RA associated genetic risk factor, PTPN22(T), further decreases the mtDNA CN, but only in carriers with established RA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaut.2018.09.008DOI Listing
January 2019

APOE Alleles and Extreme Human Longevity.

J Gerontol A Biol Sci Med Sci 2019 01;74(1):44-51

Geriatric Section, Department of Medicine, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts.

We assembled a collection of 28,297 participants from seven studies of longevity and healthy aging comprising New England Centenarian, Long Life Family, Longevity Gene Population, Southern Italian Centenarian, Japanese Centenarian, the Danish Longevity, and the Health and Retirement Studies to investigate the association between the APOE alleles ε2ε3 and ε4 and extreme human longevity and age at death. By using three different genetic models and two definitions of extreme longevity based on either a threshold model or age at death, we show that ε4 is associated with a substantially decreased odds for extreme longevity, and increased risk for death that persists even beyond ages reached by less than 1% of the population. We also show that carrying the ε2ε2 or ε2ε3 genotype is associated with significantly increased odds to reach extreme longevity, with decreased risk for death compared with carrying the genotype ε3ε3 but with only a modest reduction in risk for death beyond an age reached by less than 1% of the population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/gerona/gly174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298189PMC
January 2019

Epigenetic signature of preterm birth in adult twins.

Clin Epigenetics 2018 27;10:87. Epub 2018 Jun 27.

1Epidemiology and Biostatistics, Department of Public Health, Faculty of Health Science, University of Southern Denmark, J. B. Winsløws Vej 9B, DK-5000 Odense, Denmark.

Background: Preterm birth is a leading cause of perinatal mortality and long-term health consequences. Epigenetic mechanisms may have been at play in preterm birth survivors, and these could be persistent and detrimental to health later in life.

Methods: We performed a genome-wide DNA methylation profiling in adult twins of premature birth to identify genomic regions under differential epigenetic regulation in 144 twins with a median age of 33 years (age range 30-36).

Results: Association analysis detected three genomic regions annotated to the , and genes on chromosomes 5, 3 and 22 (FWER: 0.01, 0.02 and 0.04) respectively. These genes display strong involvement in neurodevelopmental disorders, cancer susceptibility and premature delivery. The three identified significant regions were successfully replicated in an independent sample of twins of even older age (median age 66, range 56-80) with similar regulatory patterns and nominal values < 5.05e-04. Biological pathway analysis detected five significantly enriched pathways all explicitly involved in immune responses.

Conclusion: We have found novel evidence associating premature delivery with epigenetic modification of important genes/pathways and revealed that preterm birth, as an early life event, could be related to differential methylation regulation patterns observable in adults and even at high ages which could potentially mediate susceptibility to age-related diseases and adult health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-018-0518-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020425PMC
July 2019

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

Rheumatology (Oxford) 2018 10;57(10):1861-1865

Department of Rheumatology, Odense University Hospital, Odense, Denmark.

Objectives: Surfactant protein-D (SP-D), an innate immune defence molecule of the collectin family, is expressed in lungs and additional extrapulmonary epithelia. SP-D has immune modulatory and anti-microbial effects depending on its oligomerization. The ratio of high molecular weight (HMW): low molecular weight (LMW) SP-D in serum is mainly determined by the Met11Thr polymorphism (SNP rs721917). We aimed to study the SP-D serum level and the molecular size distribution in patients with untreated axial spondyloarthritis (axSpA) as compared with control subjects.

Methods: Thirty-four patients with disease modifier untreated axSpA according to the ASAS criteria, age 19-63 years, disease duration 3.9 (2.2-5.6) years were included. Demographics, smoking habits, HLA-B27 status, ASDAS, BASDAI, BASFI, BASMI and visual analogue scale scores were recorded. SP-D in serum was measured by ELISA. DNA was isolated from whole blood and single nucleotide polymorphism rs721917 was genotyped. SP-D molecular size distribution was determined using gel filtration chromatography.

Results: SP-D in serum did not differ between patients with axSpA and healthy controls, 1177 (869, 1536) vs 910 (494, 1682) (P = 0.35) and SP-D did not correlate with disease activity. However, the HMW/LMW ratio of SP-D in serum was significantly lower in axSpA, 0.38 (0.18, 0.53) compared with controls 1.49 (0.37, 3.24) when adjusting for the Met11Thr polymorphism, gender, age, BMI and smoking (P = 0.0004). There was no correlation between HMW/LMW ratio and CRP or composite diseases outcome measures.

Conclusion: We suggest that predominance of LMW oligomeric variants of SP-D may enhance local or systemic inflammatory responses in axSpA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/key187DOI Listing
October 2018

On the power of epigenome-wide association studies using a disease-discordant twin design.

Bioinformatics 2018 12;34(23):4073-4078

Epidemiology and Biostatistics, Department of Public Health, University of Southern Denmark, Odense, Denmark.

Motivation: Many studies have investigated the association between DNA methylation alterations and disease occurrences using two design paradigms, traditional case-control and disease-discordant twins. In the disease-discordant twin design, the affected twin serves as the case and the unaffected twin serves as the control. Theoretically the twin design takes advantage of controlling for the shared genetic make-up, but it is still highly debatable if and how much researchers may benefit from such a design over the traditional case-control design.

Results: In this study, we investigate and compare the power of both designs with simulations. A liability threshold model was used assuming that identical twins share the same genetic contribution with respect to the liability of complex human diseases. Varying ranges of parameters have been used to ensure that the simulation is close to real-world scenarios. Our results reveal that the disease-discordant twin design implies greater statistical power over the traditional case-control design. For diseases with moderate and high heritability (>0.3), the disease-discordant twin design allows for large sample size reductions compared to the ordinary case-control design. Our simulation results indicate that the discordant twin design is indeed a powerful tool for epigenetic association studies.

Availability And Implementation: Computer scripts are available at https://github.com/zickyls/EWAS-Twin-Simulation.

Supplementary Information: Supplementary data are available at Bioinformatics online.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/bioinformatics/bty532DOI Listing
December 2018

Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence.

Nat Genet 2018 07 25;50(7):912-919. Epub 2018 Jun 25.

Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.

Intelligence is highly heritable and a major determinant of human health and well-being. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-018-0152-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411041PMC
July 2018

Circulating microRNAs disclose biology of normal cognitive function in healthy elderly people - a discovery twin study.

Eur J Hum Genet 2018 09 2;26(9):1378-1387. Epub 2018 May 2.

The Danish Aging Research Center and The Danish Twin Registry, Epidemiology, Biostatistics and Biodemography Unit, Department of Public Health, University of Southern Denmark, 5000, Odense, Denmark.

Neurobiology is regulated by miRNA. Here circulating plasma miRNAs were assayed on a 754 miRNA OpenArray platform using 90 monozygotic elderly twins (73-95 year of age) and associated with mini mental state examination (MMSE) and a five-component cognitive score (CCS) in an explorative study. Both ordinary individual and twin-pair analyses were performed with level of cognitive scores. Candidate miRNAs were further associated with cognitive decline over 10 years using up to six repeated assessments. A total of 278 miRNAs were expressed in plasma from at least ten participants and 23 miRNAs were nominally associated (i.e., at an uncorrected p < 0.05) with CCS or MMSE in the paired analyses. Generally, elderly individuals with poor cognitive function had increase miRNA expression compared with equivalent individuals who performed better on the cognitive scale. Three miRNAs, miR-151a-3p, miR-212-3p and miR-1274b were associated with CCS both in the paired and the individual analysis. Four miRNAs found to be associated with CCS in cross-sectional analysis were also found to show an association in longitudinal analysis such that increase miRNA expression was associated with steeper cognitive decline. We propose a shared biological path underlies dementia and normative cognitive aging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41431-018-0157-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117263PMC
September 2018

Circulating, Cell-Free Micro-RNA Profiles Reflect Discordant Development of Dementia in Monozygotic Twins.

J Alzheimers Dis 2018 ;63(2):591-601

Department of Autoimmunology and Biomarkers, Statens Serum Institut, Copenhagen, Denmark.

We aim to examine if circulating micro-RNA and cytokine levels associate with dementia diagnosis and cognitive scores. To test our hypothesis, we use plasma donated from 48 monozygotic twin pairs in 1997 and 46 micro-RNAs and 10 cytokines were quantified using microfluidic RT-qPCR and multiplex solid-phase immunoassays, respectively. Micro-RNA and cytokine profiling were examined for associations with dementia diagnoses in a longitudinal registry study or with cognitive scores at baseline. Thirty-six micro-RNAs and all cytokines were detected consistently. Micro-RNA profiles associate with diagnoses and cognitive scores at statistically significant levels while cytokine only showed trends pointing at chronic inflammation in twins having or developing dementia. The most notable findings were decreased miR-106a and miR-210, and increased miR-106b expression in twins with a dementia diagnosis. This pioneering evaluation of micro-RNA and cytokine and dementia diagnosis suggests micro-RNA targets in vasculogenesis, lipoprotein transport, and amyloid precursor protein genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-171163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127603PMC
June 2019

The genetic component of human longevity: New insights from the analysis of pathway-based SNP-SNP interactions.

Aging Cell 2018 06 25;17(3):e12755. Epub 2018 Mar 25.

Department of Biology, Ecology and Earth Sciences, University of Calabria, Rende, Italy.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/acel.12755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946073PMC
June 2018