Search

[This corrects the article DOI: 10.1371/journal.pgen.1006728.].

Major depressive disorder accelerates DNA methylation age, a biological aging marker. Subclinical depressive symptoms are common, but their link to DNA methylation aging in older adults remains unexplored. This study analyzed the cross-sectional relationship between depressive symptoms and accelerated DNA methylation aging, considering gender and race/ethnicity in U.S. adults aged over 50. We used data from 3,882 diverse participants in the 2016 Health and Retirement Study wave, measuring blood DNA methylation age against chronologic age for acceleration. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale. Multiple linear regression evaluated the association between depressive symptoms and DNA methylation age acceleration, adjusting for sociodemographic factors, blood cell proportions, and health behaviors (physical activity, alcohol use, smoking, and chronic conditions). Gender and race/ethnicity modifications were also tested. Depressive symptoms, measured by continuous CES-D score, high depressive symptoms (CES-D ≥ 4), or any symptoms (CES-D ≥ 1), significantly correlated with increased GrimAge DNA methylation age acceleration (all p ≤ .001) in unadjusted and sociodemographic-adjusted models but were nonsignificant in fully adjusted models. No significant gender or race/ethnicity effect modifications were found in fully adjusted models. Health behaviors significantly influence DNA methylation age acceleration and depressive phenotypes, underscoring the need to understand their roles in assessing psychological factors related to DNA methylation age acceleration. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Background: Incorporating genomic data into risk prediction has become an increasingly popular approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not., Methods: Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts., Results: The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p=0.006), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p < 0.001) predictive power for post-deployment PTSD., Conclusion: The inclusion of exposure variables adds to the predictive power of MRS. Classification-based MRS may be useful in predicting risk of future PTSD in populations with anticipated trauma exposure. As more data become available, including additional molecular, environmental, and psychosocial factors in these scores may enhance their accuracy in predicting PTSD and, relatedly, improve their performance in independent cohorts., (© 2024. The Author(s).)

Few studies have assessed the association of educational attainment on dementia and cognitive impairment through DNA methylation age acceleration, while accommodating exposure-mediator interaction effects. We evaluated the mediation role of six epigenetic clocks with dementia, cognitive impairment non-dementia, and normal cognition, while accommodating exposure-mediator interaction effects. To understand the joint association of low education (≤12 years) and DNA methylation age acceleration (yes/no) in relation to cognitive impairment, we used weighted logistic regression, adjusting for chronological age, sex, race/ethnicity, and cell type composition. We performed four-way mediation and interaction decomposition analysis. Analyses were conducted on 2016 venous blood study participants from the Health and Retirement Study (N = 3724). Both GrimAge acceleration (OR = 1.6 95%CI 1.3-2.1) and low educational attainment (OR = 2.4 95%CI 1.9-3.0) were associated with higher odds of cognitive impairment in a mutually adjusted logistic model. We found additive interaction associations between low education and GrimAge acceleration on dementia. We observed that 6-8% of the association of education on dementia was mediated through GrimAge acceleration. While mediation effects were small, the portion of the association of education on dementia due to additive interaction with GrimAge acceleration was between 23.6 and 29.2%. These results support the interplay of social disadvantage and biological aging processes on impaired cognition., (© 2024. The Author(s).)

Background: DNA methylation clocks have emerged as promising biomarkers for cognitive impairment and dementia. Longitudinal studies exploring the link between DNA methylation clocks and cognitive decline have been constrained by limited sample sizes and a lack of diversity., Objective: Our study aimed to investigate the longitudinal associations between DNA methylation clocks and incident cognitive impairment using a larger sample size encompassing a US nationally representative sample from the Health and Retirement Study., Methods: We measured DNA methylation age acceleration in 2016 by comparing the residuals of DNA methylation clocks, including GrimAge, against chronological age. Cognitive decline was determined by the change in Langa-Weir cognition status from 2016 to 2018. Using multivariable logistic regression, we evaluated the link between DNA methylation age acceleration and cognitive decline, adjusting for cell-type proportions, demographic, and health factors. We also conducted an inverse probability weighting analysis to address potential selection bias from varying loss-to-follow-up rates., Results: The analytic sample (N=2,713) at baseline had an average of 68 years old, and during the two years of follow-up, 12% experienced cognitive decline. Participants who experienced cognitive decline during follow-up had higher baseline GrimAge (mean = 1.2 years) acceleration compared to those who maintained normal cognitive function (mean = -0.8 years, p < 0.001). A one-year increase in GrimAge acceleration was associated with 1.05 times higher adjusted and survey-weighted odds of cognitive decline during follow-up (95% CI: 1.01-1.10). This association was consistent after accounting for loss-to-follow-up (OR = 1.07, 95% CI: 1.04-1.11)., Conclusion: Our study offers insights into DNA methylation age acceleration associated with cognitive decline, suggesting avenues for improved prevention, diagnosis, and treatment.

Background: Dementia susceptibility likely begins years before symptoms. Early life has not been comprehensively tested for dementia associations., Method: In the US Health and Retirement Study (normal baseline cognition; n=16,509; 2008-2018 waves), 31 exposures before age 16 were retrospectively assessed with ten-year incident cognitive status (dementia, impaired, normal). Using parallel logistic models, each exposure was tested with incident cognition, adjusting for sex, baseline age, follow-up, race/ethnicity, personal/parental education., Result: 14.5% had incident impairment and 5.3% had dementia. Depression was associated with 1.71 (95%CI:1.28,2.26) times higher odds of incident impairment, relative to normal cognition. Headaches/migraines were associated with 1.63 (95%CI:1.18,2.22) times higher odds of incident impairment. Learning problems were associated with 1.75 (95%CI:1.05,2.79) times higher odds of incident impairment. Childhood self-rated health of fair (1.86, 95%CI:1.27,2.64) and poor (3.39, 95%CI:1.91,5.82) were associated with higher incident dementia odds, relative to excellent., Conclusion: Early life factors may be important for impairment or dementia, extending the relevant risk window.

Growing evidence has linked inflammatory processes to cognitive decline and dementia. This work examines whether an epigenetic marker of C-reactive protein (CRP), a common clinical inflammatory biomarker, may mediate the relationship between educational attainment and cognition. We first evaluated whether 53 previously reported CRP-associated DNA methylation sites (CpGs) are associated with CRP, both individually and aggregated into a methylation risk score (MRSCRP), in 3 298 participants from the Health and Retirement Study (HRS, mean age = 69.7 years). Forty-nine CpGs (92%) were associated with the natural logarithm of CRP in HRS after adjusting for age, sex, smoking, BMI, genetic ancestry, and white blood cell counts (p < .05), and each standard deviation increase in MRSCRP was associated with a 0.38 unit increase in lnCRP (p = 4.02E-99). In cross-sectional analysis, for each standard deviation increase in MRSCRP, total memory score and total cognitive score decreased, on average, by 0.28 words and 0.43 items, respectively (p < .001). Further, MRSCRP mediated 6.9% of the relationship between high school education and total memory score in a model adjusting for age, sex, and genetic ancestry (p < .05); this was attenuated to 2.4% with additional adjustment for marital status, APOE ε4 status, health behaviors, and comorbidities (p < .05). Thus, CRP-associated methylation may partially mediate the relationship between education and cognition at older ages. Further research is warranted to determine whether DNA methylation at these sites may improve current prediction models for cognitive impairment in older adults., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Chronic inflammation and DNA methylation are potential mechanisms in dementia etiology. The linkage between inflammation and DNA methylation age acceleration in shaping dementia risk is understudied. We explored the association of inflammatory cytokines with cognitive impairment and whether DNA methylation age acceleration mediates this relationship., Methods: In a subset of the 2016 wave of the Health and Retirement Study (n=3,346, age>50), we employed logistic regression to estimate the associations between each inflammatory cytokine (interleukin-6 (IL-6), C-reactive protein (CRP), and insulin-like growth factor-1 (IGF-1)), and both Langa-Weir classified cognitive impairment non-dementia and dementia, respectively. We calculated DNA methylation age acceleration residuals by regressing GrimAge on chronologic age. We tested if DNA methylation age acceleration mediated the relationship between systemic inflammation and cognitive impairment, adjusting for sociodemographic, behavioral factors, chronic conditions, and cell type proportions., Results: The prevalence of cognitive impairment was 16%. In the fully-adjusted model, participants with a doubling of IL-6 levels had 1.12 (95% CI: 1.02-1.22) times higher odds of cognitive impairment. Similar associations were found for CRP and IGF-1. Participants with a doubling of IL-6 levels had 0.77 (95% CI: 0.64, 0.90) years of GrimAge acceleration. In mediation analyses with each cytokine as predictor separately, 17.7% (95% CI: 7.0%, 50.9%) of the effect of IL-6 on cognitive impairment was mediated through DNA methylation age acceleration. Comparable mediated estimates were found for CRP and IGF-1., Conclusions: Systemic inflammation is associated with cognitive impairment, with suggestive evidence that this relationship is partially mediated through DNA methylation age acceleration.

Cognitive impairment among older adults is a growing public health challenge and environmental chemicals may be modifiable risk factors. A wide array of chemicals has not yet been tested for association with cognition in an environment-wide association framework. In the US National Health and Nutrition Examination Survey (NHANES) 1999-2000 and 2011-2014 cross-sectional cycles, cognition was assessed using the Digit Symbol Substitution Test (DSST, scores 0-117) among participants aged 60 years and older. Concentrations of environmental chemicals measured in blood or urine were log 2 transformed and standardized. Chemicals with at least 50% of measures above the lower limit of detection were included (n chemicals =147, n classes =14). We tested for associations between chemical concentrations and cognition using parallel survey-weighted multivariable linear regression models adjusted for age, sex, race/ethnicity, education, smoking status, fish consumption, cycle year, urinary creatinine, and cotinine. Participants with at least one chemical measurement (n=4,982) were mean age 69.8 years, 55.0% female, 78.2% non-Hispanic White, and 77.0% at least high school educated. The mean DSST score was 50.4 (standard deviation (SD)=17.4). In adjusted analyses, 5 of 147 exposures were associated with DSST at p-value<0.01. Notably, a SD increase in log 2 -scaled cotinine concentration was associated with 2.71 points lower DSST score (95% CI -3.69, -1.73). A SD increase in log 2 -scaled urinary tungsten concentration was associated with 1.34 points lower DSST score (95% CI -2.11, -0.56). Exposure to environmental chemicals, particularly heavy metals and tobacco smoke, may be modifiable factors for cognition among older adults.

Background: The occurrence of post-traumatic stress disorder (PTSD) following a traumatic event is associated with biological differences that can represent the susceptibility to PTSD, the impact of trauma, or the sequelae of PTSD itself. These effects include differences in DNA methylation (DNAm), an important form of epigenetic gene regulation, at multiple CpG loci across the genome. Moreover, these effects can be shared or specific to both central and peripheral tissues. Here, we aim to identify blood DNAm differences associated with PTSD and characterize the underlying biological mechanisms by examining the extent to which they mirror associations across multiple brain regions., Methods: As the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup, we conducted the largest cross-sectional meta-analysis of epigenome-wide association studies (EWASs) of PTSD to date, involving 5077 participants (2156 PTSD cases and 2921 trauma-exposed controls) from 23 civilian and military studies. PTSD diagnosis assessments were harmonized following the standardized guidelines established by the PGC-PTSD Workgroup. DNAm was assayed from blood using either Illumina HumanMethylation450 or MethylationEPIC (850K) BeadChips. A common QC pipeline was applied. Within each cohort, DNA methylation was regressed on PTSD, sex (if applicable), age, blood cell proportions, and ancestry. An inverse variance-weighted meta-analysis was performed. We conducted replication analyses in tissue from multiple brain regions, neuronal nuclei, and a cellular model of prolonged stress., Results: We identified 11 CpG sites associated with PTSD in the overall meta-analysis (1.44e-09 < p < 5.30e-08), as well as 14 associated in analyses of specific strata (military vs civilian cohort, sex, and ancestry), including CpGs in AHRR and CDC42BPB . Many of these loci exhibit blood-brain correlation in methylation levels and cross-tissue associations with PTSD in multiple brain regions. Methylation at most CpGs correlated with their annotated gene expression levels., Conclusions: This study identifies 11 PTSD-associated CpGs, also leverages data from postmortem brain samples, GWAS, and genome-wide expression data to interpret the biology underlying these associations and prioritize genes whose regulation differs in those with PTSD., Competing Interests: Competing interests CYC is an employee of Biogen. NPD has served on scientific advisory boards for BioVie Pharma, Circular Genomics and Sentio Solutions for unrelated work. NRN serves as an unpaid member of the Ilumivu advisory board. SAMR receives support from the Wounded Warrior Project (WWP), Department of Veterans Affairs (VA), National Institute of Health (NIH), McCormick Foundation, Tonix Pharmaceuticals, Woodruff Foundation, and Department of Defense (DOD). Dr. Rauch receives royalties from Oxford University Press and American. KJR serves as a consultant for Acer, Bionomics, and Jazz Pharma; SABs for Sage, Boehringer Ingelheim, and Senseye. DJS has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, L’Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda and Vistagen. MBS has in the past 3 years received consulting income from Acadia Pharmaceuticals, Aptinyx, atai Life Sciences, BigHealth, Biogen, Bionomics, BioXcel Therapeutics, Boehringer Ingelheim, Clexio, Delix Therapeutics, Eisai, EmpowerPharm, Engrail Therapeutics, Janssen, Jazz Pharmaceuticals, NeuroTrauma Sciences, PureTech Health, Sage Therapeutics, Sumitomo Pharma, and Roche/Genentech. MBS has stock options in Oxeia Biopharmaceuticals and EpiVario. MBS has been paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry). MBS has also received research support from NIH, Department of Veterans Affairs, and the Department of Defense. MBS is on the scientific advisory board for the Brain and Behavior Research Foundation and the Anxiety and Depression Association of America.

Background: Exposure to systemic racism is linked to increased dementia burden. To assess systemic inflammation as a potential pathway linking exposure to racism and dementia disparities, we investigated the mediating role of C-reactive protein (CRP), a systemic inflammation marker, and the moderating role of the racialization process in incident dementia., Methods: In the US Health and Retirement Study (n = 6,908), serum CRP was measured at baseline (2006, 2008 waves). Incident dementia was classified by cognitive tests over a six-year follow-up. Self-reported racialized categories were a proxy for exposure to the racialization process. We decomposed racialized disparities in dementia incidence (non-Hispanic Black and/or Hispanic vs. non-Hispanic white) into 1) the mediated effect of CRP, 2) the moderated portion attributable to the interaction between racialized group membership and CRP, and 3) the controlled direct effect (other pathways through which racism operates)., Results: The 6-year cumulative incidence of dementia is 12%. Among minoritized participants (i.e., non-Hispanic Black and/or Hispanic), high CRP levels ( ≥ 75 th percentile or 4.73μg/mL) are associated with 1.26 (95%CI: 0.98, 1.62) times greater risk of incident dementia than low CRP ( < 4.73μg/mL). Decomposition analysis comparing minoritized versus non-Hispanic white participants shows that the mediating effect of CRP accounts for 3% (95% CI: 0%, 6%) of the racial disparity, while the interaction effect between minoritized group status and high CRP accounts for 14% (95% CI: 1%, 27%) of the disparity. Findings are robust to potential violations of causal mediation assumptions., Conclusions: Minoritized group membership modifies the relationship between systemic inflammation and incident dementia., (© 2024. The Author(s).)

Introduction: In observational studies, the association between alcohol consumption and dementia is mixed., Methods: We performed two-sample Mendelian randomization (MR) using summary statistics from genome-wide association studies of weekly alcohol consumption and late-onset Alzheimer's disease and one-sample MR in the Health and Retirement Study (HRS), wave 2012. Inverse variance weighted two-stage regression provided odds ratios of association between alcohol exposure and dementia or cognitively impaired, non-dementia relative to cognitively normal., Results: Alcohol consumption was not associated with late-onset Alzheimer's disease using two-sample MR (odds ratio [OR] = 1.15, 95% confidence interval [CI]: [0.78, 1.72]). In HRS, doubling weekly alcohol consumption was not associated with dementia (African ancestries, n  = 1,322, OR = 1.00, 95% CI [0.45, 2.25]; European ancestries, n  = 7,160, OR = 1.37, 95% CI [0.53, 3.51]) or cognitively impaired, non-dementia (African ancestries, n  = 1,322, OR = 1.17, 95% CI [0.69, 1.98]; European ancestries, n  = 7,160, OR = 0.75, 95% CI [0.47, 1.22])., Discussion: Alcohol consumption was not associated with cognitively impaired, non-dementia or dementia status., Highlights: Cross-sectionally in a large, diverse sample, alcohol appears protective for dementia.We apply two- and one-sample Mendelian randomization to test inferred causality.Mendelian randomization approaches show no association with alcohol and dementia.We conclude that alcohol consumption should not be considered protective., Competing Interests: The authors declare no conflicts of interest/competing interests in the production of this work. Author disclosures are available in the supporting information., (© 2024 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Dyslipidemia, which is characterized by an unfavorable lipid profile, is a key risk factor for cardiovascular disease (CVD). Understanding the relationships between epigenetic aging and lipid levels may help guide early prevention and treatment efforts for dyslipidemia., Methods: We used weighted linear regression to cross-sectionally investigate the associations between five measures of epigenetic age acceleration estimated from whole blood DNA methylation (HorvathAge Acceleration, HannumAge Acceleration, PhenoAge Acceleration, GrimAge Acceleration, and DunedinPACE) and four blood lipid measures (total cholesterol (TC), LDL-C, HDL-C, and triglycerides (TG)) in 3,813 participants (mean age = 70 years) from the Health and Retirement Study (HRS). As a sensitivity analysis, we examined the same associations in participants who fasted prior to the blood draw (n = 2,531) and in participants who did not take lipid-lowering medication (n = 1,869). Using interaction models, we also examined whether demographic factors including age, sex, and educational attainment modified the relationships between epigenetic age acceleration and blood lipids., Results: After adjusting for age, race/ethnicity, sex, fasting status, and lipid-lowering medication use, greater epigenetic age acceleration was associated with lower TC, HDL-C, and LDL-C, and higher TG (p < 0.05), although the effect sizes were relatively small (e.g., < 7 mg/dL of TC per standard deviation in epigenetic age acceleration). GrimAge acceleration and DunedinPACE associations with all lipids remained significant after further adjustment for body mass index, smoking status, and educational attainment. These associations were stronger in participants who fasted and who did not use lipid-lowering medication, particularly for LDL-C. We observed the largest number of interactions between DunedinPACE and demographic factors, where the associations with lipids were stronger in younger participants, females, and those with higher educational attainment., Conclusion: Multiple measures of epigenetic age acceleration are associated with blood lipid levels in older adults. A greater understanding of how these associations differ across demographic groups can help shed light on the relationships between aging and downstream cardiovascular diseases. The inverse associations between epigenetic age and TC and LDL-C could be due to sample limitations or non-linear relationships between age and these lipids, as both TC and LDL-C decrease faster at older ages., (© 2024. The Author(s).)

Background: Suicide is a leading cause of death worldwide. Whereas some studies have suggested that a direct measure of common genetic liability for suicide attempts (SA), captured by a polygenic risk score for SA (SA-PRS), explains risk independent of parental history, further confirmation would be useful. Even more unsettled is the extent to which SA-PRS is associated with lifetime non-suicidal self-injury (NSSI)., Methods: We used summary statistics from the largest available GWAS study of SA to generate SA-PRS for two non-overlapping cohorts of soldiers of European ancestry. These were tested in multivariable models that included parental major depressive disorder (MDD) and parental SA., Results: In the first cohort, 417 (6.3 %) of 6573 soldiers reported lifetime SA and 1195 (18.2 %) reported lifetime NSSI. In a multivariable model that included parental history of MDD and parental history of SA, SA-PRS remained significantly associated with lifetime SA [aOR = 1.26, 95%CI:1.13-1.39, p < 0.001] per standardized unit SA-PRS]. In the second cohort, 204 (4.2 %) of 4900 soldiers reported lifetime SA, and 299 (6.1 %) reported lifetime NSSI. In a multivariable model that included parental history of MDD and parental history of SA, SA-PRS remained significantly associated with lifetime SA [aOR = 1.20, 95%CI:1.04-1.38, p = 0.014]. A combined analysis of both cohorts yielded similar results. In neither cohort or in the combined analysis was SA-PRS significantly associated with NSSI., Conclusions: PRS for SA conveys information about likelihood of lifetime SA (but not NSSI, demonstrating specificity), independent of self-reported parental history of MDD and parental history of SA., Limitations: At present, the magnitude of effects is small and would not be immediately useful for clinical decision-making or risk-stratified prevention initiatives, but this may be expected to improve with further iterations. Also critical will be the extension of these findings to more diverse populations., Competing Interests: Declaration of competing interest Dr. Kessler has in the past three years received support for his epidemiological studies from Sanofi Aventis; and was a consultant for Datastat, Inc., Sage Pharmaceuticals, and Takeda. Dr. Stein has in the past three years been a paid consultant for Aptinyx, BigHealth, Biogen, Bionomics, Boehringer-Ingelheim, Cerevel Therapeutics, EmpowerPharm, Engrail Therapeutics, Genentech/Roche, GW Pharma, Janssen, Jazz Pharmaceuticals, Otsuka, Oxeia Biopharmaceuticals, PureTech Health, and Sage Therapeutics. Dr. Smoller is a member of the Scientific Advisory Board of Sensorium Therapeutics (with equity), and has received grant support from Biogen, Inc., is PI of a collaborative study of the genetics of depression and bipolar disorder sponsored by 23andMe for which 23andMe provides analysis time as in-kind support but no payments. The remaining authors have no disclosures., (Published by Elsevier B.V.)

Background and Objectives: Spouses with concordant (i.e., similar) drinking behaviors often report better quality marriages and are married longer compared with those who report discordant drinking behaviors. Less is known regarding whether concordant or discordant patterns have implications for health, as couples grow older. The present study examined whether drinking patterns among older couples are associated with mortality over time., Research Design and Methods: The Health and Retirement Study (HRS) is a nationally representative sample of individuals and their partners (married/cohabiting) over age 50 in the United States, in which participants completed surveys every 2 years. Participants included 4,656 married/cohabiting different-sex couples (9,312 individuals) who completed at least 3 waves of the HRS from 1996 to 2016. Participants reported whether they drank alcohol at all in the last 3 months, and if so, the average amount they drank per week. Mortality data were from 2016., Results: Analyses revealed concordant drinking spouses (both indicated they drank in the last 3 months) survived longer than discordant drinking spouses (1 partner drinks and the other does not) and concordant nondrinking spouses. Analysis of average drinks per week showed a quadratic association with mortality such that light drinking predicted better survival rates among individuals and their partners compared with abstaining and heavy drinking. Further, similar levels of drinking in terms of the amount of drinking were associated with greater survival, particularly among wives., Discussion and Implications: This study moves the field forward by showing that survival varies as a function of one's own and one's partner's drinking., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The prevalence and severity of many diseases differs by sex, potentially due to sex-specific patterns in DNA methylation. Autosomal sex-specific differences in DNA methylation have been observed in cord blood and placental tissue but are not well studied in saliva or in diverse populations. We sought to characterize sex-specific DNA methylation on autosomal chromosomes in saliva samples from children in the Future of Families and Child Wellbeing Study, a multi-ethnic prospective birth cohort containing an oversampling of Black, Hispanic and low-income families. DNA methylation from saliva samples was analysed on 796 children (50.6% male) at both ages 9 and 15 with DNA methylation measured using the Illumina HumanMethylation 450k array. An epigenome-wide association analysis of the age 9 samples identified 8,430 sex-differentiated autosomal DNA methylation sites ( P  < 2.4 × 10 -7 ), of which 76.2% had higher DNA methylation in female children. The strongest sex-difference was in the cg26921482 probe, in the AMDHD2 gene, with 30.6% higher DNA methylation in female compared to male children ( P  < 1 × 10 -300 ). Treating the age 15 samples as an internal replication set, we observed highly consistent results between the ages 9 and 15 measurements, indicating stable and replicable sex-differentiation. Further, we directly compared our results to previously published DNA methylation sex differences in both cord blood and saliva and again found strong consistency. Our findings support widespread and robust sex-differential DNA methylation across age, human tissues, and populations. These findings help inform our understanding of potential biological processes contributing to sex differences in human physiology and disease.

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant ( p < 5 × 10 -8 ) and suggestive ( p < 1 × 10 -6 ) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose ( FOXP1, MBOAT4, SKP2, STIM1, STX4 ), brain ( BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A ), and liver ( BRI3, FOXP1 ) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects., Competing Interests: IN is now employed by Celgene. BMP serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. SA is employed by and holds equity in 23andMe, Inc. Authors BK, MW, and CGa were employed by Helmholtz Zentrum München. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 de las Fuentes, Schwander, Brown, Bentley, Winkler, Sung, Munroe, Miller, Aschard, Aslibekyan, Bartz, Bielak, Chai, Cheng, Dorajoo, Feitosa, Guo, Hartwig, Horimoto, Kolčić, Lim, Liu, Manning, Marten, Musani, Noordam, Padmanabhan, Rankinen, Richard, Ridker, Smith, Vojinovic, Zonderman, Alver, Boissel, Christensen, Freedman, Gao, Giulianini, Harris, He, Hsu, Kühnel, Laguzzi, Li, Lyytikäinen, Nolte, Poveda, Rauramaa, Riaz, Robino, Sofer, Takeuchi, Tayo, van der Most, Verweij, Ware, Weiss, Wen, Yanek, Zhan, Amin, Arking, Ballantyne, Boerwinkle, Brody, Broeckel, Campbell, Canouil, Chai, Ida Chen, Chen, Chitrala, Concas, de Faire, de Mutsert, de Silva, de Vries, Do, Faul, Fisher, Floyd, Forrester, Friedlander, Girotto, Gu, Hallmans, Heikkinen, Heng, Homuth, Hunt, Ikram, Jacobs, Kavousi, Khor, Kilpeläinen, Koh, Komulainen, Langefeld, Liang, Liu, Liu, Lohman, Mägi, Manichaikul, McKenzie, Meitinger, Milaneschi, Nauck, Nelson, O’Connell, Palmer, Pereira, Perls, Peters, Polašek, Raitakari, Rice, Rice, Rich, Sabanayagam, Schreiner, Shu, Sidney, Sims, Smith, Starr, Strauch, Tai, Taylor, Tsai, Uitterlinden, van Heemst, Waldenberger, Wang, Wei, Wilson, Xuan, Yao, Yu, Yuan, Zhao, Becker, Bonnefond, Bowden, Cooper, Deary, Divers, Esko, Franks, Froguel, Gieger, Jonas, Kato, Lakka, Leander, Lehtimäki, Magnusson, North, Ntalla, Penninx, Samani, Snieder, Spedicati, van der Harst, Völzke, Wagenknecht, Weir, Wojczynski, Wu, Zheng, Zhu, Bouchard, Chasman, Evans, Fox, Gudnason, Hayward, Horta, Kardia, Krieger, Mook-Kanamori, Peyser, Province, Psaty, Rudan, Sim, Smith, van Dam, van Duijn, Wong, Arnett, Rao, Gauderman, Liu, Morrison, Rotter and Fornage.)

Background and Objectives: Elevated circulating cystatin C is associated with cognitive impairment in non-Hispanic Whites, but its role in racial disparities in dementia is understudied. In a nationally representative sample of older non-Hispanic White, non-Hispanic Black, and Hispanic adults in the United States, we use mediation-interaction analysis to understand how racial disparities in the cystatin C physiological pathway may contribute to racial disparities in prevalent dementia., Methods: In a pooled cross-sectional sample of the Health and Retirement Study ( n = 9,923), we employed Poisson regression to estimate prevalence ratios and to test the relationship between elevated cystatin C (>1.24 vs. ≤1.24 mg/L) and impaired cognition, adjusted for demographics, behavioral risk factors, other biomarkers, and chronic conditions. Self-reported racialized social categories were a proxy measure for exposure to racism. We calculated additive interaction measures and conducted four-way mediation-interaction decomposition analysis to test the moderating effect of race/ethnicity and mediating effect of cystatin C on the racial disparity., Results: Overall, elevated cystatin C was associated with dementia (prevalence ratio [PR] = 1.2; 95% CI: 1.0, 1.5). Among non-Hispanic Black relative to non-Hispanic White participants, the relative excess risk due to interaction was 0.7 (95% CI: -0.1, 2.4), the attributable proportion was 0.1 (95% CI: -0.2, 0.4), and the synergy index was 1.1 (95% CI: 0.8, 1.8) in a fully adjusted model. Elevated cystatin C was estimated to account for 2% (95% CI: -0, 4%) for the racial disparity in prevalent dementia, and the interaction accounted for 8% (95% CI: -5, 22%). Analyses for Hispanic relative to non-white participants suggested moderation by race/ethnicity, but not mediation., Discussion: Elevated cystatin C was associated with dementia prevalence. Our mediation-interaction decomposition analysis suggested that the effect of elevated cystatin C on the racial disparity might be moderated by race/ethnicity, which indicates that the racialization process affects not only the distribution of circulating cystatin C across minoritized racial groups, but also the strength of association between the biomarker and dementia prevalence. These results provide evidence that cystatin C is associated with adverse brain health and this effect is larger than expected for individuals racialized as minorities had they been racialized and treated as non-Hispanic White., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Higgins Tejera, Ware, Kobayashi, Fu, Hicken, Zawistowski, Mukherjee and Bakulski.)

Background: Few studies using rigorous clinical diagnosis have considered whether associations with cognitive decline are potentiated by interactions between genetic and modifiable risk factors. Given the increasing burden of cognitive impairment (CI) and dementia, we assessed whether Apolipoprotein E ε4 (APOE4) genotype status modifies the association between incident CI and key modifiable risk factors ., Methods: Older adults (70+) in the US were included. APOE4 status was genotyped. Risk factors for CI were self-reported. Cognitive status (normal, CI, or dementia) was assigned by clinical consensus panel. In eight separate Cox proportional hazard models, we assessed for interactions between APOE4 status and other CI risk factors., Result: The analytical sample included 181 participants (mean age 77.7 years; 45.9% male). APOE4 was independently associated with a greater hazard of CI in each model (Hazard Ratios [HR] between 1.81-2.66, p < 0.05) except the model evaluating educational attainment (HR 1.65, p = 0.40). The joint effects of APOE4 and high school education or less (HR 2.25, 95% CI: 1.40-3.60, p < 0.001), hypertension (HR 2.46, 95% CI: 1.28-4.73, p = 0.007), elevated depressive symptoms (HR 5.09, 95% CI: 2.59-10.02, p < 0.001), hearing loss (HR 3.44, 95% CI: 1.87-6.33, p < 0.0001), vision impairment (HR 5.14, 95% CI: 2.31-11.43, p < 0.001), smoking (HR 2.35, 95% CI: 1.24-4.47, p = 0.009), or obesity (HR 3.80, 95% CI: 2.11-6.85, p < 0.001) were associated with the hazard of incident CIND (compared to no genetic or modifiable risk factor) in separate models. The joint effect of Apolipoprotein ε4 and type 2 diabetes was not associated with CIND (HR 1.58, 95% CI: 0.67-2.48, p = 0.44)., Discussion: The combination of APOE4 and selected modifiable risk factors conveys a stronger association with incident CI than either type of risk factor alone., (© 2022. The Author(s).)

Prenatal maternal smoking is associated with low birthweight, neurological disorders, and asthma in exposed children. DNA methylation signatures can function as biomarkers of prenatal smoke exposure. However, the robustness of DNA methylation signatures across child ages, genetic ancestry groups, or tissues is not clear. Using coefficients from a meta-analysis of prenatal smoke exposure and DNA methylation in newborn cord blood, we created polymethylation scores of saliva DNA methylation from children at ages 9 and 15 in the Fragile Families and Child Wellbeing study. In the full sample at age 9 (n = 753), prenatal smoke exposure was associated with a 0.51 (95%CI: 0.35, 0.66) standard deviation higher polymethylation score. The direction and magnitude of the association was consistent in European and African genetic ancestry samples. In the full sample at age 15 (n = 747), prenatal smoke exposure was associated with a 0.48 (95%CI: 0.32, 0.63) standard deviation higher polymethylation score, and the association was attenuated among the European and Admixed-Latin genetic ancestry samples. The polymethylation score classified prenatal smoke exposure accurately (AUC age 9 = 0.77, age 15 = 0.76). Including the polymethylation score increased the AUC of base model covariates by 5 (95% CI: (2.1, 7.2)) percentage points, while including a single candidate site in the AHRR gene did not ( P -value = 0.19). Polymethylation scores for prenatal smoking were portable across genetic ancestries and more accurate than an individual DNA methylation site. Polymethylation scores from saliva samples could serve as robust and practical biomarkers of prenatal smoke exposure.

The epigenome likely interacts with traditional and genetic risk factors to influence blood pressure. We evaluated whether 13 previously reported DNA methylation sites (CpGs) are associated with systolic (SBP) or diastolic (DBP) blood pressure, both individually and aggregated into methylation risk scores (MRS), in 3070 participants (including 437 African ancestry (AA) and 2021 European ancestry (EA), mean age = 70.5 years) from the Health and Retirement Study. Nine CpGs were at least nominally associated with SBP and/or DBP after adjusting for traditional hypertension risk factors ( p < 0.05). MRS SBP was positively associated with SBP in the full sample (β = 1.7 mmHg per 1 standard deviation in MRS SBP ; p = 2.7 × 10 -5 ) and in EA (β = 1.6; p = 0.001), and MRS DBP with DBP in the full sample (β = 1.1; p = 1.8 × 10 -6 ), EA (β = 1.1; p = 7.2 × 10 -5 ), and AA (β = 1.4; p = 0.03). The MRS and BP-genetic risk scores were independently associated with blood pressure in EA. The effects of both MRSs were weaker with increased age ( p interaction < 0.01), and the effect of MRS DBP was higher among individuals with at least some college education ( p interaction = 0.02). In AA, increasing MRS SBP was associated with higher SBP in females only ( p interaction = 0.01). Our work shows that MRS is a potential biomarker of blood pressure that may be modified by traditional hypertension risk factors.

Background: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders., Methods: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors., Results: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged., Conclusions: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., (Copyright © 2021 Society of Biological Psychiatry. All rights reserved.)

Saliva is a widely used biological sample, especially in pediatric research, containing a heterogenous mixture of immune and epithelial cells. Associations of exposure or disease with saliva DNA methylation can be influenced by cell-type proportions. Here, we developed a saliva cell-type DNA methylation reference panel to estimate interindividual cell-type heterogeneity in whole saliva studies. Saliva was collected from 22 children (7-16 years) and sorted into immune and epithelial cells, using size exclusion filtration and magnetic bead sorting. DNA methylation was measured using the Illumina MethylationEPIC BeadChip. We assessed cell-type differences in DNA methylation profiles and tested for enriched biological pathways. Immune and epithelial cells differed at 181,577 (22.8%) DNA methylation sites (t-test p < 6.28 × 10 -8 ). Immune cell hypomethylated sites are mapped to genes enriched for immune pathways (p < 3.2 × 10 -5 ). Epithelial cell hypomethylated sites were enriched for cornification (p = 5.2 × 10 -4 ), a key process for hard palette formation. Saliva immune and epithelial cells have distinct DNA methylation profiles which can drive whole-saliva DNA methylation measures. A primary saliva DNA methylation reference panel, easily implemented with an R package, will allow estimates of cell proportions from whole saliva samples and improve epigenetic epidemiology studies by accounting for measurement heterogeneity by cell-type proportions.

Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10 -6 ) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function., (© 2021. The Author(s).)

Suicide is a major public health problem. The contribution of common genetic variants for major depressive disorder (MDD) independent of personal and parental history of MDD has not been established. Polygenic risk score (using PRS-CS) for MDD was calculated for US Army soldiers of European ancestry. Associations between polygenic risk for MDD and lifetime suicide attempt (SA) were tested in models that also included parental or personal history of MDD. Models were adjusted for age, sex, tranche (where applicable), and 10 principal components reflecting ancestry. In the first cohort, 417 (6.3%) of 6,573 soldiers reported a lifetime history of SA. In a multivariable model that included personal [OR = 3.83, 95% CI:3.09-4.75] and parental history of MDD [OR = 1.43, 95% CI:1.13-1.82 for one parent and OR = 1.64, 95% CI:1.20-2.26 for both parents), MDD PRS was significantly associated with SA (OR = 1.22 [95% CI:1.10-1.36]). In the second cohort, 204 (4.2%) of 4,900 soldiers reported a lifetime history of SA. In a multivariable model that included personal [OR = 3.82, 95% CI:2.77-5.26] and parental history of MDD [OR = 1.42, 95% CI:0.996-2.03 for one parent and OR = 2.21, 95% CI:1.33-3.69 for both parents) MDD PRS continued to be associated (at p = .0601) with SA (OR = 1.15 [95% CI:0.994-1.33]). A soldier's PRS for MDD conveys information about likelihood of a lifetime SA beyond that conveyed by two predictors readily obtainable by interview: personal or parental history of MDD. Results remain to be extended to prospective prediction of incident SA. These findings portend a role for PRS in risk stratification for suicide attempts., (© 2021 Wiley Periodicals LLC.)

Exposure in utero to particulate matter (PM2.5 and PM10) is associated with maladaptive health outcomes. Although exposure to prenatal PM2.5 and PM10 has cord blood DNA methylation signatures at birth, signature persistence into childhood and saliva cross-tissue applicability has not been tested. In the Fragile Families and Child Wellbeing Study, a United States 20-city birth cohort, average residential PM2.5 and PM10 during the three months prior to birth was estimated using air quality monitors with inverse distance weighting. Saliva DNA methylation at ages 9 ( n = 749) and 15 ( n = 793) was measured using the Illumina HumanMethylation 450 k BeadArray. Cumulative DNA methylation scores for particulate matter were estimated by weighting participant DNA methylation at each site by independent meta-analysis effect estimates and standardizing the sums. Using a mixed-effects regression analysis, we tested the associations between cumulative DNA methylation scores at ages 9 and 15 and PM exposure during pregnancy, adjusted for child sex, age, race/ethnicity, maternal income-to-needs ratio, nonmartial birth status, and saliva cell-type proportions. Our study sample was 50.5% male, 56.3% non-Hispanic Black, and 19.8% Hispanic, with a median income-to-needs ratio of 1.4. Mean exposure levels for PM2.5 were 27.9 μg/m 3 /day (standard deviation: 7.0; 23.7% of observations exceeded safety standards) and for PM10 were 15.0 μg/m 3 /day (standard deviation: 3.1). An interquartile range increase in PM2.5 exposure (10.73 μg/m 3 /day) was associated with a -0.0287 standard deviation lower cumulative DNA methylation score for PM2.5 (95% CI: -0.0732, 0.0158, p = 0.20) across all participants. An interquartile range increase in PM10 exposure (3.20 μg/m 3 /day) was associated with a -0.1472 standard deviation lower cumulative DNA methylation score for PM10 (95% CI: -0.3038, 0.0095, p = 0.06) across all participants. The PM10 findings were driven by the age 15 subset where an interquartile range increase in PM10 exposure was associated with a -0.024 standard deviation lower cumulative DNA methylation score for PM10 (95% CI: -0.043, -0.005, p = 0.012). Findings were robust to adjustment for PM exposure at ages 1 and 3. In utero PM10-associated DNA methylation differences were identified at age 15 in saliva. Benchmarking the timing and cell-type generalizability is critical for epigenetic exposure biomarker assessment.

Selection bias is a serious potential problem for inference about relationships of scientific interest based on samples without well-defined probability sampling mechanisms. Motivated by the potential for selection bias in: (a) estimated relationships of polygenic scores (PGSs) with phenotypes in genetic studies of volunteers and (b) estimated differences in subgroup means in surveys of smartphone users, we derive novel measures of selection bias for estimates of the coefficients in linear and probit regression models fitted to nonprobability samples, when aggregate-level auxiliary data are available for the selected sample and the target population. The measures arise from normal pattern-mixture models that allow analysts to examine the sensitivity of their inferences to assumptions about nonignorable selection in these samples. We examine the effectiveness of the proposed measures in a simulation study and then use them to quantify the selection bias in: (a) estimated PGS-phenotype relationships in a large study of volunteers recruited via Facebook and (b) estimated subgroup differences in mean past-year employment duration in a nonprobability sample of low-educated smartphone users. We evaluate the performance of the measures in these applications using benchmark estimates from large probability samples.

Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups.

Background: Altered lipid metabolism may be a risk factor for dementia, and blood cholesterol level has a strong genetic component. We tested the hypothesis that dyslipidemia (either low levels of high-density lipoprotein cholesterol (HDL-C) or high total cholesterol) is associated with cognitive status and domains, and assessed causality using genetic predisposition to dyslipidemia as an instrumental variable. Methods: Using data from European and African genetic ancestry participants in the Health and Retirement Study, we selected observations at the first non-missing biomarker assessment (waves 2006-2012). Cognition domains were assessed using episodic memory, mental status, and vocabulary tests. Overall cognitive status was categorized in three levels (normal, cognitive impairment non-dementia, dementia). Based on 2018 clinical guidelines, we compared low HDL-C or high total cholesterol to normal levels. Polygenic scores for dyslipidemia were used as instrumental variables in a Mendelian randomization framework. Multivariable logistic regressions and Wald-type ratio estimators were used to examine associations. Results: Among European ancestry participants ( n = 8,781), at risk HDL-C levels were associated with higher odds of cognitive impairment (OR = 1.20, 95% CI: 1.03, 1.40) and worse episodic memory, specifically. Using cumulative genetic risk for HDL-C levels as a valid instrumental variable, a significant causal estimate was observed between at risk low HDL-C levels and higher odds of dementia (OR = 2.15, 95% CI: 1.16, 3.99). No significant associations were observed between total cholesterol levels and cognitive status. No significant associations were observed in the African ancestry sample ( n = 2,101). Conclusion: Our study demonstrates low blood HDL-C is a potential causal risk factor for impaired cognition during aging in non-Hispanic whites of European ancestry. Dyslipidemia can be modified by changing diets, health behaviors, and therapeutic strategies, which can improve cognitive aging. Studies on low density lipoprotein cholesterol, the timing of cholesterol effects on cognition, and larger studies in non-European ancestries are needed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fu, Bakulski, Higgins and Ware.)

Objectives: This study aims to examine the relationship between childhood socioeconomic position (SEP) and cognitive function in later life within nationally representative samples of older adults in the United States and England, investigate whether these effects are mediated by later-life SEP, and determine whether social mobility from childhood to adulthood affects cognitive function and decline., Method: Using data from the Health and Retirement Study (HRS) and the English Longitudinal Survey of Ageing (ELSA), we examined the relationships between measures of SEP, cognitive performance and decline using individual growth curve models., Results: High childhood SEP was associated with higher cognitive performance at baseline in both cohorts and did not affect the rate of decline. This benefit dissipated after adjusting for education and adult wealth in the United States. Respondents with low childhood SEP, above median education, and high adult SEP had better cognitive performance at baseline than respondents with a similar childhood background and less upward mobility in both countries., Discussion: These findings emphasize the impact of childhood SEP on cognitive trajectories among older adults. Upward mobility may partially compensate for disadvantage early in life but does not protect against cognitive decline., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10 -8 ). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)