Publications by authors named "Nancy L Pedersen"

543 Publications

Long-term exposure to low-level ambient air pollution and incidence of stroke and coronary heart disease: a pooled analysis of six European cohorts within the ELAPSE project.

Lancet Planet Health 2021 Sep;5(9):e620-e632

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

Background: Long-term exposure to outdoor air pollution increases the risk of cardiovascular disease, but evidence is unclear on the health effects of exposure to pollutant concentrations lower than current EU and US standards and WHO guideline limits. Within the multicentre study Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE), we investigated the associations of long-term exposures to fine particulate matter (PM), nitrogen dioxide (NO), black carbon, and warm-season ozone (O) with the incidence of stroke and acute coronary heart disease.

Methods: We did a pooled analysis of individual data from six population-based cohort studies within ELAPSE, from Sweden, Denmark, the Netherlands, and Germany (recruited 1992-2004), and harmonised individual and area-level variables between cohorts. Participants (all adults) were followed up until migration from the study area, death, or incident stroke or coronary heart disease, or end of follow-up (2011-15). Mean 2010 air pollution concentrations from centrally developed European-wide land use regression models were assigned to participants' baseline residential addresses. We used Cox proportional hazards models with increasing levels of covariate adjustment to investigate the association of air pollution exposure with incidence of stroke and coronary heart disease. We assessed the shape of the concentration-response function and did subset analyses of participants living at pollutant concentrations lower than predefined values.

Findings: From the pooled ELAPSE cohorts, data on 137 148 participants were analysed in our fully adjusted model. During a median follow-up of 17·2 years (IQR 13·8-19·5), we observed 6950 incident events of stroke and 10 071 incident events of coronary heart disease. Incidence of stroke was associated with PM (hazard ratio 1·10 [95% CI 1·01-1·21] per 5 μg/m increase), NO (1·08 [1·04-1·12] per 10 μg/m increase), and black carbon (1·06 [1·02-1·10] per 0·5 10/m increase), whereas coronary heart disease incidence was only associated with NO (1·04 [1·01-1·07]). Warm-season O was not associated with an increase in either outcome. Concentration-response curves indicated no evidence of a threshold below which air pollutant concentrations are not harmful for cardiovascular health. Effect estimates for PM and NO remained elevated even when restricting analyses to participants exposed to pollutant concentrations lower than the EU limit values of 25 μg/m for PM and 40 μg/m for NO.

Interpretation: Long-term air pollution exposure was associated with incidence of stroke and coronary heart disease, even at pollutant concentrations lower than current limit values.

Funding: Health Effects Institute.
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http://dx.doi.org/10.1016/S2542-5196(21)00195-9DOI Listing
September 2021

Attention-deficit/hyperactivity disorder and Alzheimer's disease and any dementia: A multi-generation cohort study in Sweden.

Alzheimers Dement 2021 Sep 9. Epub 2021 Sep 9.

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

Introduction: We examined the extent to which attention-deficit/hyperactivity disorder (ADHD), a neurodevelopmental disorder, is linked with Alzheimer's disease (AD) and any dementia, neurodegenerative diseases, across generations.

Methods: A nationwide cohort born between 1980 and 2001 (index persons) were linked to their biological relatives (parents, grandparents, uncles/aunts) using Swedish national registers. We used Cox models to examine the cross-generation associations.

Results: Among relatives of 2,132,929 index persons, 3042 parents, 171,732 grandparents, and 1369 uncles/aunts had a diagnosis of AD. Parents of individuals with ADHD had an increased risk of AD (hazard ratio 1.55, 95% confidence interval 1.26-1.89). The associations attenuated but remained elevated in grandparents and uncles/aunts. The association for early-onset AD was stronger than late-onset AD. Similar results were observed for any dementia.

Discussion: ADHD is associated with AD and any dementia across generations. The associations attenuated with decreasing genetic relatedness, suggesting shared familial risk between ADHD and AD.
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http://dx.doi.org/10.1002/alz.12462DOI Listing
September 2021

A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease.

Nat Genet 2021 Sep 7;53(9):1276-1282. Epub 2021 Sep 7.

Division of Genetic Medicine, Department of Medicine Vanderbilt University Medical Center Nashville, Nashville, TN, USA.

Late-onset Alzheimer's disease is a prevalent age-related polygenic disease that accounts for 50-70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer's disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer's disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer's disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer's disease to identify further genetic variants that contribute to Alzheimer's pathology.
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http://dx.doi.org/10.1038/s41588-021-00921-zDOI Listing
September 2021

Educational attainment of same-sex and opposite-sex dizygotic twins: An individual-level pooled study of 19 twin cohorts.

Horm Behav 2021 Sep 3;136:105054. Epub 2021 Sep 3.

Psychology Department, University of Nevada Las Vegas, Nevada, USA.

Comparing twins from same- and opposite-sex pairs can provide information on potential sex differences in a variety of outcomes, including socioeconomic-related outcomes such as educational attainment. It has been suggested that this design can be applied to examine the putative role of intrauterine exposure to testosterone for educational attainment, but the evidence is still disputed. Thus, we established an international database of twin data from 11 countries with 88,290 individual dizygotic twins born over 100 years and tested for differences between twins from same- and opposite-sex dizygotic pairs in educational attainment. Effect sizes with 95% confidence intervals (CI) were estimated by linear regression models after adjusting for birth year and twin study cohort. In contrast to the hypothesis, no difference was found in women (β = -0.05 educational years, 95% CI -0.11, 0.02). However, men with a same-sex co-twin were slightly more educated than men having an opposite-sex co-twin (β = 0.14 educational years, 95% CI 0.07, 0.21). No consistent differences in effect sizes were found between individual twin study cohorts representing Europe, the USA, and Australia or over the cohorts born during the 20th century, during which period the sex differences in education reversed favoring women in the latest birth cohorts. Further, no interaction was found with maternal or paternal education. Our results contradict the hypothesis that there would be differences in the intrauterine testosterone levels between same-sex and opposite-sex female twins affecting education. Our findings in men may point to social dynamics within same-sex twin pairs that may benefit men in their educational careers.
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http://dx.doi.org/10.1016/j.yhbeh.2021.105054DOI Listing
September 2021

A genome-wide association study of the frailty index highlights brain pathways in ageing.

Aging Cell 2021 Sep 25;20(9):e13459. Epub 2021 Aug 25.

Epidemiology and Public Health Group, University of Exeter Medical School, Exeter, UK.

Frailty is a common geriatric syndrome and strongly associated with disability, mortality and hospitalization. Frailty is commonly measured using the frailty index (FI), based on the accumulation of a number of health deficits during the life course. The mechanisms underlying FI are multifactorial and not well understood, but a genetic basis has been suggested with heritability estimates between 30 and 45%. Understanding the genetic determinants and biological mechanisms underpinning FI may help to delay or even prevent frailty. We performed a genome-wide association study (GWAS) meta-analysis of a frailty index in European descent UK Biobank participants (n = 164,610, 60-70 years) and Swedish TwinGene participants (n = 10,616, 41-87 years). FI calculation was based on 49 or 44 self-reported items on symptoms, disabilities and diagnosed diseases for UK Biobank and TwinGene, respectively. 14 loci were associated with the FI (p < 5*10 ). Many FI-associated loci have established associations with traits such as body mass index, cardiovascular disease, smoking, HLA proteins, depression and neuroticism; however, one appears to be novel. The estimated single nucleotide polymorphism (SNP) heritability of the FI was 11% (0.11, SE 0.005). In enrichment analysis, genes expressed in the frontal cortex and hippocampus were significantly downregulated (adjusted p < 0.05). We also used Mendelian randomization to identify modifiable traits and exposures that may affect frailty risk, with a higher educational attainment genetic risk score being associated with a lower degree of frailty. Risk of frailty is influenced by many genetic factors, including well-known disease risk factors and mental health, with particular emphasis on pathways in the brain.
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http://dx.doi.org/10.1111/acel.13459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441299PMC
September 2021

Changes in leisure-time physical activity during the adult life span and relations to cardiovascular risk factors-Results from multiple Swedish studies.

PLoS One 2021 19;16(8):e0256476. Epub 2021 Aug 19.

Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.

Objective: To evaluate how self-reported leisure-time physical activity (PA) changes during the adult life span, and to study how PA is related to cardiovascular risk factors using longitudinal studies.

Methods: Several Swedish population-based longitudinal studies were used in the present study (PIVUS, ULSAM, SHE, and SHM, ranging from hundreds to 30,000 participants) to represent information across the adult life span in both sexes. Also, two cross-sectional studies were used as comparison (EpiHealth, LifeGene). PA was assessed by questionnaires on a four or five-level scale.

Results: Taking results from several samples into account, an increase in PA from middle-age up to 70 years was found in males, but not in females. Following age 70, a decline in PA was seen. Young adults reported both a higher proportion of sedentary behavior and a higher proportion high PA than the elderly. Females generally reported a lower PA at all ages. PA was mainly associated with serum triglycerides and HDL-cholesterol, but also weaker relationships with fasting glucose, blood pressure and BMI were found. These relationships were generally less strong in elderly subjects.

Conclusion: Using data from multiple longitudinal samples the development of PA over the adult life span could be described in detail and the relationships between PA and cardiovascular risk factors were portrayed. In general, a higher or increased physical activity over time was associated with a more beneficial cardiovascular risk factor profile, especially lipid levels.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256476PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375969PMC
August 2021

Genetic insights into biological mechanisms governing human ovarian ageing.

Nature 2021 08 4;596(7872):393-397. Epub 2021 Aug 4.

Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
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http://dx.doi.org/10.1038/s41586-021-03779-7DOI Listing
August 2021

Sex differences in genetic and environmental influences on frailty and its relation to body mass index and education.

Aging (Albany NY) 2021 07 6;13(13):16990-17023. Epub 2021 Jul 6.

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

Frailty is influenced by numerous genetic and environmental factors. However, sex differences in how these factors affect frailty, and the gene-environment interplay among frailty and two of its well-established risk factors, unhealthy body mass index (BMI) and low education, are less clear. In a large sample of 42,994 Swedish twins, we used structural equation models to estimate the genetic (heritability) and environmental sources of variance in frailty, defined as the frailty index (FI), separately in men and women. Genetic and individual-specific environmental factors contributed approximately equally to the FI variance. The heritability of FI was slightly, but significantly, higher in women (52%) than in men (45%), yet we found only weak-to-no indication of different sources of genetic variance influencing frailty across sexes. We observed a small-to-moderate genetic overlap between FI and BMI, and that the correlation between FI and education was largely explained by environmental factors common to twins in a pair. Additionally, genetic factors accounted for more of FI variation at both low and high BMI levels, with similar patterns in both sexes. In conclusion, the twin-based heritability of frailty is higher in women than in men, and different mechanisms may underlie the associations of frailty with BMI and education.
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http://dx.doi.org/10.18632/aging.203262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312411PMC
July 2021

Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging.

Genome Biol 2021 06 29;22(1):194. Epub 2021 Jun 29.

Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.

Background: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field.

Results: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels.

Conclusion: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.
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http://dx.doi.org/10.1186/s13059-021-02398-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243879PMC
June 2021

Frailty trajectories in three longitudinal studies of aging: Is the level or the rate of change more predictive of mortality?

Age Ageing 2021 Jun 11. Epub 2021 Jun 11.

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

Background: frailty shows an upward trajectory with age, and higher levels increase the risk of mortality. However, it is less known whether the shape of frailty trajectories differs by age at death or whether the rate of change in frailty is associated with mortality.

Objectives: to assess population frailty trajectories by age at death and to analyse whether the current level of the frailty index (FI) i.e. the most recent measurement or the person-specific rate of change is more predictive of mortality.

Methods: 3,689 individuals from three population-based cohorts with up to 15 repeated measurements of the Rockwood frailty index were analysed. The FI trajectories were assessed by stratifying the sample into four age-at-death groups: <70, 70-80, 80-90 and >90 years. Generalised survival models were used in the survival analysis.

Results: the FI trajectories by age at death showed that those who died at <70 years had a steadily increasing trajectory throughout the 40 years before death, whereas those who died at the oldest ages only accrued deficits from age ~75 onwards. Higher level of FI was independently associated with increased risk of mortality (hazard ratio 1.68, 95% confidence interval 1.47-1.91), whereas the rate of change was no longer significant after accounting for the current FI level. The effect of the FI level did not weaken with time elapsed since the last measurement.

Conclusions: Frailty trajectories differ as a function of age-at-death category. The current level of FI is a stronger marker for risk stratification than the rate of change.
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http://dx.doi.org/10.1093/ageing/afab106DOI Listing
June 2021

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

A coordinated analysis of the associations among personality traits, cognitive decline, and dementia in older adulthood.

J Res Pers 2021 Jun 23;92. Epub 2021 Apr 23.

Northwestern University.

There are individual differences in the rates of cognitive decline across later adulthood. Personality traits are among the factors that may account for these differences. The current project investigated whether personality traits were associated with trajectories of cognitive decline, and whether the associations were different before and after dementia diagnosis. The data was analyzed using linear mixed effects regression. Across study aims is a focus on replicability and generalizability. Each question was addressed in four independent longitudinal studies (EAS, MAP, ROS, SATSA), then meta-analyzed, providing estimates of replicability. Results indicated that low neuroticism and high openness were associated with total cognitive function. We detected evidence for cognitive decline in all four samples, and openness was associated with decline post dementia diagnosis.
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http://dx.doi.org/10.1016/j.jrp.2021.104100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168939PMC
June 2021

Neuroticism, Smoking, and the Risk of Parkinson's Disease.

J Parkinsons Dis 2021 ;11(3):1325-1334

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

Background: The relationship among neuroticism, smoking, and Parkinson's disease (PD) is less examined.

Objective: To examine the causal associations between neuroticism, smoking initiation, and the risk of PD.

Methods: We performed a two-sample Mendelian randomization (MR) design in a network framework. Summary statistics from meta-analyses of genome-wide association studies (GWAS) were based on large cohorts of European ancestry. Study participants were from various cohort studies for neuroticism and smoking initiation, and case-control studies or cohort studies of PD from previously published GWAS meta-analyses. Patients with PD were ascertained from either clinical visit or self-reported.

Results: The two-sample MR analysis showed no evidence for a causal association between neuroticism and PD risk (odds ratio [OR] 0.86, 95%confidence intervals [CIs] 0.67 to 1.12). While we did not find a significant association between neuroticism and PD, one SNP, rs58879558 (located in MAPT region), was associated with both neuroticism and PD. We found a significant association of neuroticism on smoking initiation (OR: 1.10, 95%CI: 1.05 to 1.14). Further, our results provided evidence for a protective effect of smoking initiation on the risk of PD (OR: 0.75, 95%CI: 0.62 to 0.91).

Conclusion: These findings do not support a causal association of neuroticism on PD risk. However, they provide evidence for a causal relationship between neuroticism and smoking initiation and a strong causal effect of smoking initiation on a reduced risk of PD.
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http://dx.doi.org/10.3233/JPD-202522DOI Listing
January 2021

Epigenome-wide association study of level and change in cognitive abilities from midlife through late life.

Clin Epigenetics 2021 Apr 21;13(1):85. Epub 2021 Apr 21.

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

Background: Epigenetic mechanisms are important in aging and may be involved in late-life changes in cognitive abilities. We conducted an epigenome-wide association study of leukocyte DNA methylation in relation to level and change in cognitive abilities, from midlife through late life in 535 Swedish twins.

Results: Methylation levels were measured with the Infinium Human Methylation 450 K or Infinium MethylationEPIC array, and all sites passing quality control on both arrays were selected for analysis (n = 250,816). Empirical Bayes estimates of individual intercept (age 65), linear, and quadratic change were obtained from latent growth curve models of cognitive traits and used as outcomes in linear regression models. Significant sites (p < 2.4 × 10) were followed up in between-within twin pair models adjusting for familial confounding and full-growth modeling. We identified six significant associations between DNA methylation and level of cognitive abilities at age 65: cg18064256 (PPP1R13L) with processing speed and spatial ability; cg04549090 (NRXN3) with spatial ability; cg09988380 (POGZ), cg25651129 (-), and cg08011941 (ENTPD8) with working memory. The genes are involved in neuroinflammation, neuropsychiatric disorders, and ATP metabolism. Within-pair associations were approximately half that of between-pair associations across all sites. In full-growth curve models, associations between DNA methylation and cognitive level at age 65 were of small effect sizes, and associations between DNA methylation and longitudinal change in cognitive abilities of very small effect sizes.

Conclusions: Leukocyte DNA methylation was associated with level, but not change in cognitive abilities. The associations were substantially attenuated in within-pair analyses, indicating they are influenced in part by genetic factors.
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http://dx.doi.org/10.1186/s13148-021-01075-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061224PMC
April 2021

Body Mass Index Differentially Moderates Heritability of Total Joint Replacement Due to Hip and Knee Osteoarthritis: A Cohort Study of 29,893 Swedish Twin Pairs.

J Bone Joint Surg Am 2021 Jul;103(14):1319-1327

Section of Orthopedics, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.

Background: Osteoarthritis and obesity are diseases with high prevalence, and they share common etiologies. We investigated the sex-specific genetic susceptibility to hip and knee osteoarthritis necessitating total joint replacement (TJR), and how body mass index (BMI) moderated the heritability of these osteoarthritis phenotypes.

Methods: We linked 29,893 twin pairs with information on BMI in the Swedish Twin Registry with the Swedish National Patient Register to identify twins who underwent primary TJR of the hip or knee combined with a concomitant diagnosis of primary osteoarthritis of these joints. Structural equation modeling was used to calculate the heritability of hip and knee osteoarthritis treated with TJR, with estimates adjusted for the first available BMI, birth year, and sex. We also investigated how heritability varied with BMI treated as a continuous variable.

Results: Similar heritability estimates for hip replacement (0.65 [95% confidence interval (CI), 0.59 to 0.70]) and knee replacement (0.57 [95% CI, 0.50 to 0.64]) were found. Heritability decreased with higher BMI in both sexes for hip replacement and in men for knee replacement. In contrast, heritability for knee replacement increased with higher BMI in women; the estimate was 0.37 (90% likelihood interval [LI], 0.25 to 0.49) for a BMI of 20 kg/m2 and 0.87 (90% LI, 0.68 to 0.94) for a BMI of 35 kg/m2.

Conclusions: In our population, heritability explained, on average, about half of the susceptibility to undergo primary TJR of the hip or knee with the indication of primary osteoarthritis, but it varied with BMI and sex. We demonstrated substantial heritability for knee replacement in obese women.

Level Of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.2106/JBJS.20.00946DOI Listing
July 2021

Clinical biomarkers and associations with healthspan and lifespan: Evidence from observational and genetic data.

EBioMedicine 2021 Apr 1;66:103318. Epub 2021 Apr 1.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. Electronic address:

Background: Biomarker-disease relationships are extensively investigated. However, associations between common clinical biomarkers and healthspan, the disease-free lifespan, are largely unknown. We aimed to explore the predictive values of ten biomarkers on healthspan and lifespan, and to identify putative causal mechanisms.

Methods: Using data from 12,098 Swedish individuals aged 47-94 years, we examined both serum concentrations and genetically predicted levels of ten glycemic, lipid-, inflammatory, and hematological biomarkers. During a follow-up period of up to 16 years, 3681 incident cases of any chronic disease (i.e., end of healthspan) and 2674 deaths (i.e., end of lifespan) were documented. Cox regression models were applied to estimate the associations of a one standard deviation increase in biomarkers with healthspan and lifespan.

Findings: Seven out of ten serum biomarkers were significantly associated with risks of any chronic disease and death; elevated glycemic biomarkers and high-density lipoprotein-related biomarkers showed the strongest detrimental (hazard ratio [HR] 1·29 [95% CI 1·24-1·34]) and protective effects (HR 0·92 [95% CI 0·89-0·96]), respectively. Genetic predisposition to elevated fasting blood glucose (FBG) was associated with increased risks of any chronic disease (HR 1·05 [95% CI 1·02-1·09]); genetically determined higher C-reactive protein correlated with lower death risks (HR 0·91 [95% CI 0·87-0·95]). Notably, the genetically proxied FBG-healthspan association was largely explained by serum FBG concentration.

Interpretation: Circulating concentrations of glycemic, lipid-, and inflammatory biomarkers are predictive of healthspan and lifespan. Glucose control is a putative causal mechanism and a potential intervention target for healthspan maintenance.

Funding: This study was supported by the Swedish Research Council (2015-03,255, 2018-02,077), FORTE (2013-2292), the Loo & Hans Osterman Foundation, the Foundation for Geriatric Diseases, the Magnus Bergwall Foundation, the Strategic Research Program in Epidemiology at Karolinska Institutet (SH, JJ), the China Scholarship Council, and the Swedish National Graduate School for Competitive Science on Ageing and Health. The Swedish Twin Registry is managed by Karolinska Institutet and receives funding as an infrastructure through the Swedish Research Council, 2017-00,641.
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http://dx.doi.org/10.1016/j.ebiom.2021.103318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047464PMC
April 2021

Association Between Microscopic Colitis and Parkinson's Disease in a Swedish Population.

Mov Disord 2021 08 25;36(8):1919-1926. Epub 2021 Mar 25.

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

Background: Gastrointestinal inflammation has been linked with Parkinson's disease (PD). Microscopic colitis (MC) is an intestinal inflammatory disease with unknown relationship with PD.

Objective: This study aimed to examine the association of MC with PD risk.

Methods: In this nationwide matched cohort study in Sweden, PD incidence was compared between 12,609 patients with histologically confirmed MC and a matched population cohort of 58,879 MC-free individuals and a sibling cohort comprising all unaffected siblings of the MC patients (N /N  = 6281/12,351). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models.

Results: During a mean follow-up of ~7 years, we identified 449 incident PD diagnoses among the MC patients and the population cohort. Overall, MC was associated with an adjusted HR of 1.76 for PD, but the association attenuated substantially during follow-up. In the time-varying effects model, PD hazard was 3.45-fold (95% CI: 2.42, 4.93) higher during the first 2 years after biopsy and 1.80-fold (95% CI: 1.23, 2.64) higher during the following 3 years among MC versus MC-free individuals but was not different beyond 5 years after biopsy (HR: 1.03; 95% CI: 0.68, 1.54). This temporal pattern of MC-PD associations persisted when comparing MC patients to their siblings. In a post hoc case-control analysis, we also detected a strong association between MC and preexisting PD (odds ratio: 3.46; 95% CI: 2.91, 4.12).

Conclusions: Our findings suggest that MC may not be a risk factor for PD; instead, it may co-occur with PD as a comorbidity or develop after a diagnosis of PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28594DOI Listing
August 2021

Association of life-course depression with the risk of dementia in late life: A nationwide twin study.

Alzheimers Dement 2021 08 3;17(8):1383-1390. Epub 2021 Mar 3.

Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China.

Introduction: Whether depression is a prodromal phase or risk factor for dementia is under debate. We aimed to unveil the nature of depression-dementia association by looking into the time window of depression occurrence.

Methods: Dementia-free twins (n = 41,727) from the Swedish Twin Registry were followed-up for 18 years. Data were analyzed using generalized estimating equation (GEE) for all individuals and conditional logistic regression for co-twin matched pairs.

Results: In the GEE model, multi-adjusted odds ratios (ORs; 95% confidence intervals [CIs]) of dementia were 1.46 (1.09-1.95) for mid-life, 2.16 (1.82-2.56) for late-life, 2.24 (1.49-3.36) for mid- to late-life, and 2.65 (1.17-5.98) for lifelong depression. The ORs in conditional logistic regression and in GEE did not differ significantly (P = 0.60). Education ≥8 years attenuated dementia risk associated with mid-life depression.

Discussion: Not only late-life depression, but also mid-life depression is associated with dementia. Genetic and early-life environmental factors could not account for this association. Education ≥8 years might buffer the impact of mid-life depression on dementia.
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http://dx.doi.org/10.1002/alz.12303DOI Listing
August 2021

Subjective hearing ability, physical and mental comorbidities in individuals with bothersome tinnitus in a Swedish population sample.

Prog Brain Res 2021 4;260:51-78. Epub 2021 Feb 4.

Tinnitus Center, Charité-Universitätsmedizin Berlin, Berlin, Germany. Electronic address:

Objective: This study investigates associations of subjective hearing ability, physical comorbidities, and mental comorbidities with bothersome (vs. non-bothersome) tinnitus and mediating effects between these influences.

Methods: The Swedish LifeGene cohort was used to sample cross-sectional survey data (collected 2009-2016) of 7615 participants with tinnitus, 697 (9.2%) of whom rated their tinnitus as bothersome. Associations between bothersome tinnitus and subjective hearing ability, physical and mental comorbidities were investigated by separate age- and gender-adjusted multiple logistic regression models. Interrelationships between these associations were investigated by logistic mediation models.

Results: Compared to non-bothersome tinnitus, bothersome tinnitus was associated with higher age, reduced subjective hearing ability, hearing-related difficulties in social situations, cardiovascular disease, chronic shoulder pain, thyroid disease, Ménière's disease, depression, anxiety syndrome, and social anxiety. Subjective hearing impairment or hearing-related difficulties mediated 13-36% of the effects of mental comorbidities on bothersome tinnitus. Depression or anxiety syndrome mediated 5-8% of most relationships between physical comorbidities and bothersome tinnitus. Depression, anxiety syndrome, or social anxiety mediated 2-4% of the effects of subjective hearing impairment or hearing-related difficulties on bothersome tinnitus.

Conclusion: Psychological factors, subjective hearing impairment, and hearing-related difficulties in social situations play key roles in predicting bothersome (vs. non-bothersome) tinnitus in a large population sample. Psychological factors contribute to explaining the impact of physical comorbidities and hearing-related effects on bothersome tinnitus. This highlights their transdiagnostic importance for aggravating varied physical symptom clusters. Interventions to improve or prevent high tinnitus burden should be interdisciplinary/multimodal and target auditory, physical, and psychological factors.
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http://dx.doi.org/10.1016/bs.pbr.2020.10.001DOI Listing
February 2021

Job Strain and Trajectories of Cognitive Change Before and After Retirement.

J Gerontol B Psychol Sci Soc Sci 2021 Aug;76(7):1313-1322

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

Objectives: We examined associations between job strain and trajectories of change in cognitive functioning (general cognitive ability plus verbal, spatial, memory, and speed domains) before and after retirement.

Methods: Data on indicators of job strain, retirement age, and cognitive factors were available from 307 members of the Swedish Adoption/Twin Study of Aging. Participants were followed up for up to 27 years (mean = 15.4, SD = 8.5).

Results: In growth curve analyses controlling for age, sex, education, depressive symptoms, cardiovascular health, and twinness, greater job strain was associated with general cognitive ability (estimate = -1.33, p = .002), worse memory (estimate = -1.22, p = .007), speed (estimate = -1.11, p = .012), and spatial ability (estimate = -0.96, p = .043) at retirement. Greater job strain was also associated with less improvement in general cognitive ability before retirement and a somewhat slower decline after retirement. The sex-stratified analyses showed that the smaller gains of general cognitive ability before retirement (estimate = -1.09, p = .005) were only observed in women. Domain-specific analyses revealed that greater job strain was associated with less improvement in spatial (estimate = -1.35, p = .010) and verbal (estimate = -0.64, p = .047) ability before retirement in women and a slower decline in memory after retirement in women (estimate = 0.85, p = .008) and men (estimate = 1.12, p = .013). Neither preretirement nor postretirement speed was affected significantly by job strain.

Discussion: Greater job strain may have a negative influence on overall cognitive functioning prior to and at retirement, while interrupting exposure to job strain (postretirement) may slow the rate of cognitive aging. Reducing the level of stress at work should be seen as a potential target for intervention to improve cognitive aging outcomes.
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http://dx.doi.org/10.1093/geronb/gbab033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363035PMC
August 2021

Tumor Necrosis Factor Inhibition and Parkinson Disease: A Mendelian Randomization Study.

Neurology 2021 03 19;96(12):e1672-e1679. Epub 2021 Feb 19.

From the Departments of Medical Epidemiology and Biostatistics (X.K., A.P., N.L.P., K.W., D.M.W.) and Clinical Neuroscience (K.W.), Karolinska Institutet, Stockholm, Sweden; Laboratory of Neurogenetics (S.B.-C.), National Institute on Aging, National Institutes of Health, Bethesda, MD; Instituto de Investigación Biosanitaria de Granada (S.B.-C.), Spain; Preventive Neurology Unit (A.J.N.), Wolfson Institute of Preventive Medicine, Queen Mary University of London; Department of Clinical and Movement Neurosciences (A.J.N.), UCL Institute of Neurology, London; and MRC Unit for Lifelong Health and Ageing (D.M.W.), University College London, UK.

Objective: To evaluate the effects of long-term tumor necrosis factor (TNF) inhibition on the risk and age at onset of Parkinson disease (PD), we performed a 2-sample Mendelian randomization study using genome-wide association studies (GWAS) summary statistics.

Methods: Genetic variants in the vicinity of , the gene encoding TNF receptor 1 (TNFR1), were identified as predictive of pharmacologic blockade of TNFR1 signaling by anti-TNF therapy, based on genetic associations with lower circulating C-reactive protein (CRP; GWAS n = 204,402). The effects of TNF-TNFR1 inhibition were estimated for PD risk (n/ = 37,688/981,372) and age at PD onset (n = 28,568) using GWAS data from the International Parkinson's Disease Genomics Consortium and 23andMe, Inc. To validate variants as proxies of long-term anti-TNF treatment, we also assessed whether variant associations reflected anticipated effects of TNFR1 inhibition on Crohn disease, ulcerative colitis, and multiple sclerosis risk (n = 38,589-45,975).

Results: TNF-TNFR1 signaling inhibition was not estimated to affect PD risk (odds ratio [OR] per 10% lower circulating CRP = 0.99; 95% confidence interval [CI] 0.91-1.08) or age at onset (0.13 years later onset; 95% CI -0.66 to 0.92). In contrast, genetically indexed TNF-TNFR1 signaling blockade predicted reduced risk of Crohn disease (OR 0.75; 95% CI 0.65-0.86) and ulcerative colitis (OR 0.84; 95% CI 0.74-0.97) and increased multiple sclerosis risk (OR 1.57; 95% CI 1.36-1.81). Findings were consistent across models using different genetic instruments and Mendelian randomization estimators.

Conclusions: Our findings do not imply that TNF-TNFR1 signaling inhibition will prevent or delay PD onset.

Classification Of Evidence: This study provides Class II evidence that TNF-TNFR1 signaling inhibition is not associated with the risk or age at onset of PD.
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http://dx.doi.org/10.1212/WNL.0000000000011630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032365PMC
March 2021

Trajectories of Big Five Personality Traits: A Coordinated Analysis of 16 Longitudinal Samples.

Eur J Pers 2020 May 1;34(3):301-321. Epub 2020 May 1.

Northwestern University, Chicago, IL USA.

This study assessed change in self-reported Big Five personality traits. We conducted a coordinated integrative data analysis using data from 16 longitudinal samples, comprising a total sample of over 60 000 participants. We coordinated models across multiple datasets and fit identical multi-level growth models to assess and compare the extent of trait change over time. Quadratic change was assessed in a subset of samples with four or more measurement occasions. Across studies, the linear trajectory models revealed declines in conscientiousness, extraversion, and openness. Non-linear models suggested late-life increases in neuroticism. Meta-analytic summaries indicated that the fixed effects of personality change are somewhat heterogeneous and that the variability in trait change is partially explained by sample age, country of origin, and personality measurement method. We also found mixed evidence for predictors of change, specifically for sex and baseline age. This study demonstrates the importance of coordinated conceptual replications for accelerating the accumulation of robust and reliable findings in the lifespan developmental psychological sciences.
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http://dx.doi.org/10.1002/per.2259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869960PMC
May 2020

Loss of a co-twin at birth and subsequent risk of psychiatric disorders.

Elife 2021 Jan 28;10. Epub 2021 Jan 28.

Center of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík, Iceland.

Twins suffering a co-twin loss at birth have reported feelings of loneliness and grief while it remains unexplored if they suffer increased risk of psychiatric disorders. We contrasted rate of first-onset psychiatric disorders among all Swedish-born twins whose co-twin died within 60 days after birth between 1973 and 2011 (n = 787) to that of 3935 matched unexposed twins, 3935 matched singletons (both matched to the exposed twins by birth year, sex, and birth characteristics), and 880 full siblings of the exposed twins. During a median of 19-year follow-up, exposed twins were at increased risk of first-onset psychiatric disorders (hazard ratio = 1.56, 95%CI 1.30-1.87) compared with unexposed twins. We observed the strongest association for emotional disorders and for psychiatric disorders diagnosed before the age of 25. Comparisons with matched singletons and the twin's full siblings rendered similar results, corroborating an association of loss of a co-twin at birth with subsequent risk of psychiatric disorders.
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http://dx.doi.org/10.7554/eLife.63514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843130PMC
January 2021

Genome-wide association study of patients with a severe major depressive episode treated with electroconvulsive therapy.

Mol Psychiatry 2021 Jun 22;26(6):2429-2439. Epub 2021 Jan 22.

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

Although large genome-wide association studies (GWAS) of major depressive disorder (MDD) have identified many significant loci, the SNP-based heritability remains notably low, which might be due to etiological heterogeneity in existing samples. Here, we test the utility of targeting the severe end of the MDD spectrum through genome-wide SNP genotyping of 2725 cases who received electroconvulsive therapy (ECT) for a major depressive episode (MDE) and 4035 controls. A subset of cases (n = 1796) met a narrow case definition (MDE occurring in the context of MDD). Standard GWAS quality control procedures and imputation were conducted. SNP heritability and genetic correlations with other traits were estimated using linkage disequilibrium score regression. Results were compared with MDD cases of mild-moderate severity receiving internet-based cognitive behavioral therapy (iCBT) and summary results from the Psychiatric Genomics Consortium (PGC). The SNP-based heritability was estimated at 29-34% (SE: 6%) for the narrow case definition, considerably higher than the 6.5-8.0% estimate in the most recent PGC MDD study. Our severe MDE cases had smaller genetic correlations with neurodevelopmental disorders and neuroticism than PGC MDD cases but higher genetic risk scores for bipolar disorder than iCBT MDD cases. One genome-wide significant locus was identified (rs114583506, P = 5e-8) in an intron of HLA-B in the major histocompatibility locus on chr6. These results indicate that individuals receiving ECT for an MDE have higher burden of common variant risk loci than individuals with mild-moderate MDD. Furthermore, severe MDE shows stronger relations with other severe adult-onset psychiatric disorders but weaker relations with personality and stress-related traits than mild-moderate MDD. These findings suggest a different genetic architecture at the severest end of the spectrum, and support further study of the severest MDD cases as an extreme phenotype approach to understand the etiology of MDD.
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http://dx.doi.org/10.1038/s41380-020-00984-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295407PMC
June 2021

Adaptation of the Charlson Comorbidity Index for Register-Based Research in Sweden.

Clin Epidemiol 2021 12;13:21-41. Epub 2021 Jan 12.

Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

Purpose: Comorbidity indices are often used to measure comorbidities in register-based research. We aimed to adapt the Charlson comorbidity index (CCI) to a Swedish setting.

Methods: Four versions of the CCI were compared and evaluated by disease-specific experts.

Results: We created a cohesive coding system for CCI to 1) harmonize the content between different international classification of disease codes (ICD-7,8,9,10), 2) delete incorrect codes, 3) enhance the distinction between mild, moderate or severe disease (and between diabetes with and without end-organ damage), 4) minimize duplication of codes, and 5) briefly explain the meaning of individual codes in writing.

Conclusion: This work may provide an integrated and efficient coding algorithm for CCI to be used in medical register-based research in Sweden.
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http://dx.doi.org/10.2147/CLEP.S282475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812935PMC
January 2021

DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan.

Mol Psychiatry 2021 Jun 8;26(6):2148-2162. Epub 2021 Jan 8.

Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33520, Finland.

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.
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http://dx.doi.org/10.1038/s41380-020-00987-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263810PMC
June 2021

Irritable bowel syndrome and Parkinson's disease risk: register-based studies.

NPJ Parkinsons Dis 2021 Jan 5;7(1). Epub 2021 Jan 5.

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

To examine whether irritable bowel syndrome (IBS) was related to the future risk of Parkinson's disease (PD), we conducted a nested case-control study in the Swedish total population including 56,564 PD cases identified from the Swedish Patient Register and 30 controls per case individually matched by sex and year of birth. Odds ratios (ORs) with 95% confidence intervals (CIs) for having a prior diagnosis of IBS were estimated using conditional logistic regression. We furthermore conducted a cohort study using the Swedish Twin Registry following 3046 IBS patients identified by self-reported abdominal symptoms and 41,179 non-IBS individuals. Through Cox proportional hazard models, we estimated hazard ratios (HRs) and 95% CIs for PD risk. In the nested case-control study, 253 (0.4%) PD cases and 5204 (0.3%) controls had a previous IBS diagnosis. IBS diagnosis was associated with a 44% higher risk of PD (OR = 1.44, 95% CI 1.27-1.63). Temporal relationship analyses showed 53% and 38% increased risk of PD more than 5 and 10 years after IBS diagnosis, respectively. In the cohort analysis based on the Swedish Twin Registry, there was no statistically significantly increased risk of PD related to IBS (HR = 1.25, 95% CI = 0.87-1.81). Our results suggest a higher risk of PD diagnosis after IBS. These results provide additional evidence supporting the importance of the gut-brain axis in PD.
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http://dx.doi.org/10.1038/s41531-020-00145-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785733PMC
January 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

A geroscience approach for Parkinson's disease: Conceptual framework and design of PROPAG-AGEING project.

Mech Ageing Dev 2021 03 29;194:111426. Epub 2020 Dec 29.

Consorzio Interuniversitario Risonanze Magnetiche di Metalloproteine (CIRMMP), Florence, Italy.

Advanced age is the major risk factor for idiopathic Parkinson's disease (PD), but to date the biological relationship between PD and ageing remains elusive. Here we describe the rationale and the design of the H2020 funded project "PROPAG-AGEING", whose aim is to characterize the contribution of the ageing process to PD development. We summarize current evidences that support the existence of a continuum between ageing and PD and justify the use of a Geroscience approach to study PD. We focus in particular on the role of inflammaging, the chronic, low-grade inflammation characteristic of elderly physiology, which can propagate and transmit both locally and systemically. We then describe PROPAG-AGEING design, which is based on the multi-omic characterization of peripheral samples from clinically characterized drug-naïve and advanced PD, PD discordant twins, healthy controls and "super-controls", i.e. centenarians, who never showed clinical signs of motor disability, and their offspring. Omic results are then validated in a large number of samples, including in vitro models of dopaminergic neurons and healthy siblings of PD patients, who are at higher risk of developing PD, with the final aim of identifying the molecular perturbations that can deviate the trajectories of healthy ageing towards PD development.
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http://dx.doi.org/10.1016/j.mad.2020.111426DOI Listing
March 2021
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