Biology subjects

Hagg, S.

Publications and source records attributed to Hagg, S..

11 recordsLinked to original sources

bioRxiv2025

Heritability of human lifespan is about 50% when confounding factors are addressed

The heritability of human lifespan is a fundamental question in biology. Current estimates of heritability are low - twin studies show that about 20-25% of the variation in lifespan is explained by genetics, and some large family pedigree studies suggest it is as low as 7%. However, these studies do not distinguish between deaths driven by intrinsic biological processes and deaths caused by extrinsic factors such as accidents or infections. Here we use mathematical modeling and analyses of twin cohorts raised together and apart to show that extrinsic mortality skews heritability estimates by driving down measured lifespan correlations among twin pairs. We also identify a nonlinear effect of the cutoff age--the minimum age of death included in each study -- on estimates of heritability. Correcting for these factors more than doubles previous estimates, revealing that intrinsic heritability of human lifespan is above 50%. Such high heritability is similar to most other complex human traits. We thus challenge the consensus that genetics has only a minor effect on lifespan and show that genes explain the majority of lifespan variation. Since genes are important, understanding the genetics of longevity can reveal aging mechanisms and inform medicine and public health.

genetics↗

bioRxiv2021

A computational solution for bolstering reliability of epigenetic clocks: Implications for clinical trials and longitudinal tracking

Epigenetic clocks are widely used aging biomarkers calculated from DNA methylation data. Unfortunately, measurements for individual CpGs can be surprisingly unreliable due to technical noise, and this may limit the utility of epigenetic clocks. We report that noise produces deviations up to 3 to 9 years between technical replicates for six major epigenetic clocks. The elimination of low-reliability CpGs does not ameliorate this issue. Here, we present a novel computational multi-step solution to address this noise, involving performing principal component analysis on the CpG-level data followed by biological age prediction using principal components as input. This method extracts shared systematic variation in DNAm while minimizing random noise from individual CpGs. Our novel principal-component versions of six clocks show agreement between most technical replicates within 0 to 1.5 years, equivalent or improved prediction of outcomes, and more stable trajectories in longitudinal studies and cell culture. This method entails only one additional step compared to traditional clocks, does not require prior knowledge of CpG reliabilities, and can improve the reliability of any existing or future epigenetic biomarker. The high reliability of principal component-based epigenetic clocks will make them particularly useful for applications in personalized medicine and clinical trials evaluating novel aging interventions.

bioinformatics↗

bioRxiv2020

Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance

Somatically acquired whole chromosome loss in nucleated blood cells is an indicator of immune aging and genomic instability. However, little is known about aging, lifestyle and genetic factors influencing mitochondrial (MT) DNA abundance. In this study, MT DNA abundance was estimated from the weighted intensities of probes mapping to the MT genome in 295,150 participants from the UK Biobank. We found that abundance of MT DNA was significantly elevated in women compared to men, was negatively correlated with advanced age, more packyears, greater body-mass index, higher frailty index as well as elevated red and white blood cell count and, importantly, lower mortality. In addition, several biochemistry markers in blood related to cholesterol metabolism, ion homeostasis and kidney function were found to be significantly associated with MT DNA abundance. By performing a genome-wide association study, we identified 50 independent regions genome-wide significantly associated with MT DNA abundance which harbour multiple genes involved in the immune system, cancer as well as mitochondrial function. Using mixed effects models, we estimated the SNP-heritability of MT DNA abundance to be around 8%. To investigate the consequence of altered MT DNA abundance, we performed a phenome-wide association study and found that MT DNA abundance is involved in risk for leukaemia, hematologic diseases as well as hypertension. Thus, estimating MT DNA abundance from genotyping arrays has the potential to provide novel insights into age- and disease relevant processes, particularly those related to immunity and established mitochondrial functions.

genomics↗

bioRxiv2019

Implicit bias is strongest when assessing top candidates

BackgroundAcademic life is highly competitive and expectations of fair competition underlie the assumption that academia is a meritocracy. However, implicit bias reinforces gender inequality in all peer review processes, unfairly eliminating outstanding individuals and depleting academia of diversity. Here, we ask whether applicant gender biases reviewer assessments of merit in Sweden, a country that is top ranked for gender equality. MethodsWe analyzed the peer review procedure for positions awarded at a Swedish medical University, Karolinska Institutet (KI), during four consecutive years (2014-2017) for Assistant Professor (n=207) and Senior Researcher (n=153). We derived a composite bibliometric score to compute productivity, and compared this to subjective external (non-KI) peer reviewer scores on applicants merits to test their association for men and women, separately. ResultsMen and women with equal merits are not scored equally by reviewers. Men generally have stronger associations (steeper slopes) between computed productivity and subjective external scores, meaning that peer reviewers suitably "reward" mens productivity with increased merit scores. However, for each additional composite bibliometric score point, women applying for Assistant Professor positions only receive 58% (79% for Senior Researcher) of the external reviewer score that men received, confirming that implicit bias affects external reviewers assessments. As productivity increases, the difference in merit scores between men and women increases. ConclusionsAccumulating bias impacts most strongly in the highest tier of competition, the pool from which successful candidates are ultimately chosen. Gender bias is apparent in external peer review processes of applications for academic positions in Sweden, and is likely to reinforce the unbalanced numbers of professorships in Sweden.

scientific communication and education↗

bioRxiv2019

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

Summary/AbstractO_ST_ABSBackgroundC_ST_ABSEpigenetic 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. MethodsWe 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. ResultsOverall, 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 5,037 sites that showed the greatest heritable/familial-environmental influences (p<1E-07) were enriched for immune and inflammation pathways while 2,020 low stability sites showed enrichment in stress-related pathways. ConclusionsAcross 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.

genetics↗

bioRxiv2019

Human Aging DNA Methylation Signatures are Conserved but Accelerated in Cultured Fibroblasts

Aging is associated with progressive and site-specific changes in DNA methylation (DNAm). These global changes are captured by DNAm clocks that accurately predict chronological age in humans but relatively little is known about how clocks perform in vitro. Here we culture primary human fibroblasts across the cellular lifespan ([~]6 months) and use four different DNAm clocks to show that age-related DNAm signatures are conserved and accelerated in vitro. The Skin & Blood clock shows the best linear correlation with chronological time (r=0.90), including during replicative senescence. Although similar in nature, the rate of epigenetic aging is approximately 62x times faster in cultured cells than in the human body. Consistent with in vivo data, cells aged under hyperglycemic conditions exhibit an approximately three years elevation in baseline DNAm age. Moreover, candidate gene-based analyses further corroborate the conserved but accelerated biological aging process in cultured fibroblasts. Fibroblasts mirror the established DNAm topology of the age-related ELOVL2 gene in human blood and the rapid hypermethylation of its promoter cg16867657, which correlates with a linear decrease in ELOVL2 mRNA levels across the lifespan. Using generalized additive modeling on twelve timepoints across the lifespan, we also show how single CpGs exhibit loci-specific, linear and nonlinear trajectories that reach rates up to -47% (hypomethylation) to +23% (hypermethylation) per month. Together, these high temporal resolution global, gene-specific, and single CpG data highlight the conserved and accelerated nature of epigenetic aging in cultured fibroblasts, which may constitute a system to evaluate age-modifying interventions across the lifespan.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC=\"FIGDIR/small/605295_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (60K):\norg.highwire.dtl.DTLVardef@101e4f2org.highwire.dtl.DTLVardef@15df049org.highwire.dtl.DTLVardef@4a704dorg.highwire.dtl.DTLVardef@112f970_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract\n\nC_FIG

cell biology↗

bioRxiv2019

Neuroticism as a predictor of frailty in old age: a genetically informative approach

ObjectiveNeuroticism is associated with poor health outcomes, but its contribution to the accumulation of health deficits in old age, i.e. frailty, is largely unknown. We aimed to explore associations between neuroticism and frailty cross-sectionally and over up to 29 years, and to investigate the contribution of shared genetic influences. MethodData were derived from the UK Biobank (UKB, n=502,631), the Australian Over 50s Study (AO50, n=3,011) and the Swedish Twin Registry (SALT n=23,744, SATSA n=1,637). Associations between neuroticism and the Frailty Index were investigated using regression analysis cross-sectionally in UKB, AO50 and SATSA, and longitudinally in SALT (25-29y follow-up) and SATSA (6 and 23y follow-up). The co-twin control method was applied to explore the contribution of underlying shared familial factors (SALT, SATSA, AO50). Genome-wide polygenic risk scores for neuroticism in all samples were used to further assess whether common genetic variants associated with neuroticism predict frailty. ResultsHigh neuroticism was consistently associated with greater frailty cross-sectionally (adjusted {beta}, 95% confidence intervals in UKB= 0.32, 0.32-0.33; AO50= 0.35, 0.31-0.39; SATSA= 0.33, 0.27-0.39) and longitudinally up to 29 years (SALT= 0.24; 0.22-0.25; SATSA 6y= 0.31, 0.24-0.38; SATSA 23y= 0.16, 0.07-0.25). When controlling for underlying shared genetic and environmental factors the neuroticism-frailty association remained significant, although decreased. Polygenic risk scores for neuroticism significantly predicted frailty in the two larger samples (meta-analyzed total {beta}= 0.06, 0.05-0.06). ConclusionHigh neuroticism is associated with the development and course of frailty. Both environmental and genetic influences, including neuroticism-associated genetic variants, contribute to this relationship.

epidemiology↗

bioRxiv2018

Genetic meta-analysis identifies 10 novel loci and functional pathways for Alzheimer’s disease risk

Late onset Alzheimers disease (AD) is the most common form of dementia with more than 35 million people affected worldwide, and no curative treatment available. AD is highly heritable and recent genome-wide meta-analyses have identified over 20 genomic loci associated with AD, yet only explaining a small proportion of the genetic variance indicating that undiscovered loci exist. Here, we performed the largest genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 AD cases, 383,378 controls). AD-by-proxy status is based on parental AD diagnosis, and showed strong genetic correlation with AD (rg=0.81). Genetic meta analysis identified 29 risk loci, of which 9 are novel, and implicating 215 potential causative genes. Independent replication further supports these novel loci in AD. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver and microglia). Furthermore, gene-set analyses indicate the genetic contribution of biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomisation results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying more of the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD to guide new drug development.

genetics↗

bioRxiv2017

A frailty index for UK Biobank participants

BackgroundFrailty indices (FIs) measure variation in health between aging individuals. Researching FIs in resources with large-scale genetic and phenotypic data will provide insights into the causes and consequences of frailty. Thus, we aimed to develop an FI using UK Biobank data, a cohort study of 500,000 middle-aged and older adults.\n\nMethodsAn FI was calculated using 49 self-reported questionnaire items on traits covering health, presence of diseases and disabilities, and mental wellbeing, according to standard protocol. We used multiple imputation to derive FI values for the entire eligible sample in the presence of missing item data (N =500,336). To validate the measure, we assessed associations of the FI with age, sex, and risk of all-cause mortality (follow-up [≤] 9.7 years) using linear and Cox proportional hazards regression models.\n\nResultsMean FI in the cohort was 0.125 (standard deviation = 0.075), and there was a curvilinear trend towards higher values in older participants. FI values were also marginally higher on average in women than men. In survival models, 10% higher baseline frailty (i.e. a 0.1 FI increment) was associated with higher risk of death (hazard ratio (HR) = 1.65; 95% confidence interval: 1.62, 1.68). Associations were stronger in younger participants than in old, and in men compared to women (HRs: 1.72 vs. 1.56, respectively).\n\nConclusionsThe FI is a valid measure of frailty in UK Biobank. The cohorts data are open-access for researchers to use, and we provide script for deriving this tool to facilitate future studies on frailty.

epidemiology↗

bioRxiv2017

The frailty index is associated with the need for care in an aging Swedish population

BackgroundThe Rockwood frailty index (FI) has proven a valid predictor of mortality, institutionalization and requirement for health services. However, little is known about the relationship between the FI and the need for care - an indication of dependency. To this end, we ascertained the associations between the FI and the need for current and future care.\n\nMethodsA Rockwood-based FI was tested for association with the current need for care and care needs in the future during a 23-year follow-up in the Swedish Adoption/Twin Study of Aging (n=1477; 623 men, 854 women; aged 29-95 years at baseline). Need for care was defined as receiving help at least once a week in daily routines. Age, sex, education, living alone, smoking status and body mass index were considered as covariates.\n\nResultsThe FI was independently associated with current need for care (OR=1.27 for accumulation of one deficit, 95%CI 1.20-1.34) and future need for care (HR=1.12 for accumulation of one deficit, 95%CI 1.08-1.15). Co-twin control analyses confirmed the results; the pair member currently needing care had higher median FI levels compared to their co-twin not needing care, and the pair member having higher baseline FI had shorter median time to the onset of future care need compared to their co-twin with lower FI.\n\nConclusionsThe FI is a determinant of current care needs and predictive of care needs in the future. The FI may thus represent a risk indicator for dependency and offer an amenable target for preventive measures.

epidemiology↗

bioRxiv2017

Frailty index as a predictor of all-cause and cause-specific mortality in a Swedish population-based cohort

BackgroundFrailty is a complex manifestation of aging and associated with increased risk of mortality and poor health outcomes. Younger individuals (under 65 years) typically have low levels of frailty and are less-studied in this respect. Also, the relationship between the Rockwood frailty index (FI) and cause-specific mortality in community settings is understudied.\n\nMethodsWe created and validated a 42-item Rockwood-based FI in The Swedish Adoption/Twin Study of Aging (n=1477; 623 men, 854 women; aged 29-95 years) and analyzed its association with all-cause and cause-specific mortality in up to 30-years of follow-up. Deaths due to cardiovascular disease (CVD), cancer, dementia and other causes were considered as competing risks.\n\nResultsOur FI demonstrated construct validity as its associations with age, sex and mortality were similar to the existing literature. The FI was independently associated with increased risk for all-cause mortality in younger (<65 years; HR per increase in one deficit 1.11, 95%CI 1.07-1.17) and older ([≥]65 years; HR 1.07, 95%CI 1.04-1.10) women and in younger men (HR 1.05, 95%CI 1.01-1.10). In cause-specific mortality analysis, the FI was strongly predictive of CVD mortality in women (HR per increase in one deficit 1.13, 95%CI 1.09-1.17), whereas in men the risk was restricted to deaths from other causes (HR 1.07, 95%CI 1.01-1.13).\n\nConclusionsThe FI showed good predictive value for all-cause mortality especially in the younger group. The FI predicted CVD mortality risk in women, whereas in men it captured vulnerability to death from various causes.

epidemiology↗