Epigenome-wide meta-analysis of prenatal maternal stressful life events and newborn DNA methylation.

Prenatal maternal stressful life events are associated with adverse neurodevelopmental outcomes in offspring. Biological mechanisms underlying these associations are largely unknown, but DNA methylation likely plays a role. This meta-analysis included twelve non-overlapping cohorts from ten independent longitudinal studies (N = 5,496) within the international Pregnancy and Childhood Epigenetics consortium to examine maternal stressful life events during pregnancy and DNA methylation in cord blood. Children whose mothers reported higher levels of cumulative maternal stressful life events during pregnancy exhibited differential methylation of cg26579032 in ALKBH3. Stressor-specific domains of conflict with family/friends, abuse (physical, sexual, and emotional), and death of a close friend/relative were also associated with differential methylation of CpGs in APTX, MyD88, and both UHRF1 and SDCCAG8, respectively; these genes are implicated in neurodegeneration, immune and cellular functions, regulation of global methylation levels, metabolism, and schizophrenia risk. Thus, differences in DNA methylation at these loci may provide novel insights into potential mechanisms of neurodevelopment in offspring.

Environmental chemical-wide associations with immune biomarkers in US adults: A cross-sectional analysis.

Environmental chemical exposures influence immune system functions, and humans are exposed to a wide range of chemicals, termed the chemical "exposome". A comprehensive, discovery analysis of the associations of multiple chemical families with immune biomarkers is needed. In this study, we tested the associations between environmental chemical concentrations and immune biomarkers. We analyzed the United States cross-sectional National Health and Nutrition Examination Survey (NHANES, 1999-2018). Chemical biomarker concentrations were measured in blood or urine (196 chemicals, 17 chemical families). Immune biomarkers included counts of lymphocytes, neutrophils, monocytes, basophils, eosinophils, red blood cells, white blood cells, and mean corpuscular volume. We conducted separate survey-weighted, multivariable linear regressions of each log2-transformed chemical and immune measure, adjusted for relevant covariates. We accounted for multiple comparisons using a false discovery rate (FDR). Among 45,528 adult participants, the mean age was 45.7 years, 51.4% were female, and 69.3% were Non-Hispanic White. 71 (36.2%) chemicals were associated with at least one of the eight immune biomarkers. The most chemical associations (FDR<0.05) were observed with mean corpuscular volume (36 chemicals) and red blood cell counts (35 chemicals). For example, a doubling in the concentration of cotinine was associated with 0.16 fL (95% CI: 0.15, 0.17; FDR<0.001) increased mean corpuscular volume, and a doubling in the concentration of blood lead was associated with 61,736 increased red blood cells per µL (95% CI: 54,335, 69,138; FDR<0.001). A wide variety of chemicals, such as metals and smoking-related compounds, were highly associated with immune system biomarkers. This environmental chemical-wide association study identified chemicals from multiple families for further toxicological, immunologic, and epidemiological investigation.

Exposure to heavy metals in utero and autism spectrum disorder at age 3: a meta-analysis of two longitudinal cohorts of siblings of children with autism.

BACKGROUND: Autism spectrum disorder (ASD) is a prevalent and heterogeneous neurodevelopmental disorder. Risk is attributed to genetic and prenatal environmental factors, though the environmental agents are incompletely characterized. METHODS: In Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk in Babies Learning Early Signs (MARBLES), two pregnancy cohorts of siblings of children with ASD, urinary metals concentrations during two pregnancy time periods (< 28 weeks and ≥ 28 weeks of gestation) were measured using inductively coupled plasma mass spectrometry. At age three, clinicians assessed ASD with DSM-5 criteria. In an exposure-wide association framework, using multivariable log binomial regression, we examined each metal for association with ASD status, adjusting for gestational age at urine sampling, child sex, age at pregnancy, race/ethnicity and education. We meta-analyzed across the two cohorts. RESULTS: In EARLI (n = 170) 17% of children were diagnosed with ASD, and 44% were classified as having non-neurotypical development (Non-TD). In MARBLES (n = 231), 21% were diagnosed with ASD, and 14% classified as Non-TD. During the first and second trimester period (< 28 weeks), having cadmium concentration over the level of detection was associated with 1.69 (1.08, 2.64) times higher risk of ASD, and 1.29 (0.95, 1.75)times higher risk of Non-TD. A doubling of first and second trimester cesium concentration was marginally associated with 1.89 (0.94, 3.80) times higher risk of ASD, and a doubling of third trimester cesium with 1.69 (0.97, 2.95) times higher risk of ASD. CONCLUSION: Exposure in utero to elevated levels of cadmium and cesium, as measured in urine collected during pregnancy, was associated with increased risk of developing ASD.

Blood-based biomarkers for Alzheimer's disease and cognitive function from mid- to late life.

INTRODUCTION: We investigated associations of Alzheimer's disease (AD) serum biomarkers with longitudinal changes in cognitive function from mid- to late life among women. METHODS: The study population included 192 women with the median age of 53.3 years at baseline, from the Study of Women's Health Across the Nation Michigan Cohort, followed up over 14 years. Associations between baseline serum amyloid ß (Aß)42, the Aß42/40 ratio, phosphorylated tau181 (p-tau181), and total tau with longitudinal changes in cognition were evaluated using linear mixed effects models. RESULTS: After adjusting for confounders, lower Aß42/40 ratios were associated with faster declines in the Digit Span Backward Test. Higher p-tau181 also showed a borderline statistically significant association with more rapid decline in the Symbol Digit Modalities Test. DISCUSSION: Our findings suggest that mid-life serum AD biomarkers could be associated with accelerated cognitive decline from mid- to late life in women. Future studies with larger samples are needed to validate and extend our findings. HIGHLIGHTS: This study investigates midlife serum AD biomarkers on longitudinal cognitive function changes in women. Mid-life serum AD biomarkers are associated with accelerated cognitive decline. A decrease in the Aß42/40 ratio was associated with a faster decline in the DSB score. A higher p-tau181 concentration was associated with a faster decline in the SDMT score.

Developmental programming: Impact of prenatal bisphenol-A exposure on liver and muscle transcriptome of female sheep.

Gestational Bisphenol A (BPA) exposure leads to peripheral insulin resistance, and hepatic and skeletal muscle oxidative stress and lipotoxicity during adulthood in the female sheep offspring. To investigate transcriptional changes underlying the metabolic outcomes, coding and non-coding (nc) RNA in liver and muscle from 21-month-old control and prenatal BPA-treated (0.5 mg/kg/day from days 30 to 90 of gestation; Term: 147 days) female sheep were sequenced. Prenatal BPA-treatment dysregulated: expression of 194 genes (138 down, 56 up) in liver and 112 genes (32 down, 80 up) in muscle (FDR < 0.05 and abs log2FC > 0.5); 155 common gene pathways including mitochondrial-related genes in both tissues; 1415 gene pathways including oxidative stress and lipid biosynthetic process specifically in the liver (FDR < 0.01); 192 gene pathways including RNA biosynthetic processes in muscle (FDR < 0.01); 77 lncRNA (49 down, 28 up), 14 microRNAs (6 down, 8 up), 127 snoRNAs (63 down, 64 up) and 55 snRNAs (15 down, 40 up) in the liver while upregulating 6 lncRNA and dysregulating 65 snoRNAs (47 down, 18 up) in muscle (FDR < 0.1, abs log2FC > 0.5). Multiple ncRNA correlated with LCORL, MED17 and ZNF41 mRNA in liver but none of them in the muscle. Discriminant analysis identified (p < 0.05) PECAM, RDH11, ABCA6, MIR200B, and MIR30B in liver and CAST, NOS1, FASN, MIR26B, and MIR29A in muscle as gene signatures of gestational BPA exposure. These findings provide mechanistic clues into the development and/or maintenance of the oxidative stress and lipid accumulation and potential for development of mitochondrial and fibrotic defects contributing to the prenatal BPA-induced metabolic dysfunctions.

DNA methylation changes associated with prenatal mercury exposure: A meta-analysis of prospective cohort studies from PACE consortium.

Mercury (Hg) is a ubiquitous heavy metal that originates from both natural and anthropogenic sources and is transformed in the environment to its most toxicant form, methylmercury (MeHg). Recent studies suggest that MeHg exposure can alter epigenetic modifications during embryogenesis. In this study, we examined associations between prenatal MeHg exposure and levels of cord blood DNA methylation (DNAm) by meta-analysis in up to seven independent studies (n = 1462) as well as persistence of those relationships in blood from 7 to 8 year-old children (n = 794). In cord blood, we found limited evidence of differential DNAm at cg24184221 in MED31 (ß = 2.28 × 10-4, p-value = 5.87 × 10-5) in relation to prenatal MeHg exposure. In child blood, we identified differential DNAm at cg15288800 (ß = 0.004, p-value = 4.97 × 10-5), also located in MED31. This repeated link to MED31, a gene involved in lipid metabolism and RNA Polymerase II transcription function, may suggest a DNAm perturbation related to MeHg exposure that persists into early childhood. Further, we found evidence for association between prenatal MeHg exposure and child blood DNAm levels at two additional CpGs: cg12204245 (ß = 0.002, p-value = 4.81 × 10-7) in GRK1 and cg02212000 (ß = -0.001, p-value = 8.13 × 10-7) in GGH. Prenatal MeHg exposure was associated with DNAm modifications that may influence health outcomes, such as cognitive or anthropometric development, in different populations.

Transcriptional profiling of the response to the trichloroethylene metabolite S-(1,2-dichlorovinyl)-L-cysteine revealed activation of the eIF2α/ATF4 integrated stress response in two in vitro placental models.

Trichloroethylene (TCE) is an industrial solvent and widespread environmental contaminant. Although TCE exposure is prevalent, epidemiological studies of TCE exposure associations with adverse birth outcomes are inconclusive. Prior studies show that the TCE metabolite S-(1,2-dichlorovinyl)-L-cysteine (DCVC) exhibits toxicity in a placental cell line. In the current study, genome-wide gene expression and gene set enrichment analyses were used to identify novel genes and pathway alterations in the HTR-8/SVneo human trophoblast cell line and human placental villous explants treated with DCVC at concentrations relevant to human exposures. In the cells, concentration- and time-dependent effects were observed, as evidenced by the magnitude of altered gene expression after treatment with 20 µM DCVC versus 10 µM, and 12-h versus 6-h of treatment. Comparing the two models for the transcriptional response to 12-h 20 µM DCVC treatment, no differentially expressed genes reached significance in villous explants, whereas 301 differentially expressed genes were detected in HTR-8/SVneo cells compared with non-treated controls (FDR < 0.05 + LogFC > 0.35 [FC > 1.3]). GSEA revealed five upregulated enriched pathways in common between explants and cells (FDR < 0.05). Moreover, all 12-h DCVC treatment groups from both models contained upregulated pathways enriched for genes regulated by the ATF4 transcription factor. The overrepresentation of ATF4 regulation of differentially expressed genes indicated activation of the integrated stress response (ISR), a condition triggered by multiple stress stimuli, including the unfolded protein response. DCVC-induced ISR activation was confirmed by elevated eIF2α phosphorylation, ATF4 protein concentrations, and decreased global protein synthesis in HTR-8/SVneo cells. This study identifies a mechanism of DCVC-induced cytotoxicity by revealing the involvement of a specific stress signaling pathway.

Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease.

BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts. METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts. RESULTS: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts. CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.

Estimation of Eosinophil Cells in Cord Blood with References Based on Blood in Adults via Bayesian Measurement Error Modeling.

MOTIVATION: Eosinophils are phagocytic white blood cells with a variety of roles in the immune system. In situations where actual counts are not available, high quality approximations of their cell proportions using indirect markers are critical. RESULTS: We develop a Bayesian measurement error model to estimate proportions of eosinophils in cord blood, using the cord blood DNA methylation profiles, based on markers of eosinophil cell heterogeneity in blood of adults. The proposed method can be directly extended to other cells across different reference panels. We demonstrate the method's estimation accuracy using B cells and show that the findings support the proposed approach. The method has been incorporated into the estimateCellCounts function in the minfi package to estimate eosinophil cells proportions in cord blood. AVAILABILITY: estimateCellCounts function is implemented and available in Bioconductor package minfi. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Menopausal hormone therapy prior to the diagnosis of ovarian cancer is associated with improved survival.

PURPOSE: Prior studies of menopausal hormone therapy (MHT) and ovarian cancer survival have been limited by lack of hormone regimen detail and insufficient sample sizes. To address these limitations, a comprehensive analysis of 6419 post-menopausal women with pathologically confirmed ovarian carcinoma was conducted to examine the association between MHT use prior to diagnosis and survival. METHODS: Data from 15 studies in the Ovarian Cancer Association Consortium were included. MHT use was examined by type (estrogen-only (ET) or estrogen+progestin (EPT)), duration, and recency of use relative to diagnosis. Cox proportional hazards models were used to estimate the association between hormone therapy use and survival. Logistic regression and mediation analysis was used to explore the relationship between MHT use and residual disease following debulking surgery. RESULTS: Use of ET or EPT for at least five years prior to diagnosis was associated with better ovarian cancer survival (hazard ratio, 0.80; 95% CI, 0.74 to 0.87). Among women with advanced stage, high-grade serous carcinoma, those who used MHT were less likely to have any macroscopic residual disease at the time of primary debulking surgery (p for trend <0.01 for duration of MHT use). Residual disease mediated some (17%) of the relationship between MHT and survival. CONCLUSIONS: Pre-diagnosis MHT use for 5+ years was a favorable prognostic factor for women with ovarian cancer. This large study is consistent with prior smaller studies, and further work is needed to understand the underlying mechanism.

Identification of environmental chemicals targeting miscarriage genes and pathways using the comparative toxicogenomics database.

BACKGROUND: Miscarriage is a prevalent public health issue and many events occur before women are aware of their pregnancy, complicating research design. Thus, risk factors for miscarriage are critically understudied. Our goal was to identify environmental chemicals with a high number of interactions with miscarriage genes, based on known toxicogenomic responses. METHODS: We used miscarriage (MeSH: D000022) and chemical gene lists from the Comparative Toxicogenomics Database in human, mouse, and rat. We assessed enrichment for gene ontology biological processes among the miscarriage genes. We prioritized chemicals (n = 25) found at Superfund sites or in the blood or urine pregnant women. For chemical-disease gene sets of sufficient size (n = 13 chemicals, n = 20 comparisons), chi-squared enrichment tests and proportional reporting ratios (PRR) were calculated. We cross-validated enrichment results. RESULTS: Miscarriage was annotated with 121 genes and overrepresented in inflammatory response (q = 0.001), collagen metabolic process (q = 1 × 10-13), cell death (q = 0.02), and vasculature development (q = 0.005) pathways. The number of unique genes annotated to a chemical ranged from 2 (bromacil) to 5607 (atrazine). In humans, all chemicals tested were highly enriched for miscarriage gene overlap (all p < 0.001; parathion PRR = 7, cadmium PRR = 6.5, lead PRR = 3.9, arsenic PRR = 3.5, atrazine PRR = 2.8). In mice, highest enrichment (p < 0.001) was observed for naphthalene (PRR = 16.1), cadmium (PRR = 12.8), arsenic (PRR = 11.6), and carbon tetrachloride (PRR = 7.7). In rats, we observed highest enrichment (p < 0.001) for cadmium (PRR = 8.7), carbon tetrachloride (PRR = 8.3), and dieldrin (PRR = 5.3). Our findings were robust to 1000 permutations each of variable gene set sizes. CONCLUSION: We observed chemical gene sets (parathion, cadmium, naphthalene, carbon tetrachloride, arsenic, lead, dieldrin, and atrazine) were highly enriched for miscarriage genes. Exposures to chemicals linked to miscarriage, and thus linked to decreased probability of live birth, may limit the inclusion of fetuses susceptible to adverse birth outcomes in epidemiology studies. Our findings have critical public health implications for successful pregnancies and the interpretation of adverse impacts of environmental chemical exposures on pregnancy.

Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium.

Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother-child pairs), we meta-analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1 kg/m2), P < 1.06 × 10-7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of the association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for acausal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites. In conclusion, this well-powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large-scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology.

DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis.

Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.

Cadmium and Alzheimer's disease mortality in U.S. adults: Updated evidence with a urinary biomarker and extended follow-up time.

Cadmium has been linked to impaired cognitive function in adults and may cause behavioral, physiological and molecular abnormalities characteristic of Alzheimer's disease (AD) in animals. Evidence linking cadmium and AD in humans is limited, but supportive. In the most recent epidemiologic study, blood cadmium in U.S. adults was positively associated with elevated AD mortality 7-13 years later. The association between urinary cadmium - an arguably more appropriate biomarker for studying chronic diseases - and AD mortality has not yet been explored. Further study of cadmium and AD mortality in an independent population, with longer follow-up, and stratified by sex is also needed. We sought to answer these questions using the U.S. National Health and Nutrition Examination Survey (NHANES) (1999-2006 cycles) and NHANES III (interviews in 1988-1994) datasets, separately linked to AD mortality as of 2011. We used survey-weighted Cox regression models predicting age at AD death and adjusted for race/ethnicity, sex, smoking status, education and urinary creatinine. An interquartile range (IQR; IQR=0.51ng/mL) increase in urinary cadmium was associated with 58% higher rate of AD mortality (hazard ratio (HR)=1.58, 95% CI: 1.20, 2.09. p-value=0.0009, mean follow-up: 7.5 years) in NHANES 1999-2006 participants. In contrast, in NHANES III participants, an IQR (IQR=0.78ng/mL) increase in urinary cadmium was not associated with AD mortality (HR=0.85, 95% CI: 0.63, 1.17, p-value=0.31, mean follow-up: 13 years). Also in the NHANES III sample however, when the maximum follow-up time was restricted to 12.7 years (i.e. the same as NHANES 1999-2006 participants) and urinary creatinine adjustments were not made, urinary cadmium was associated with elevated AD mortality (HR=1.11, 95% CI: 1.02, 1.20, p-value=0.0086). Our study partially supported an association between cadmium and AD mortality, but the sensitivity of results to follow-up time and creatinine adjustments necessitate cautious interpretation of the association. Further studies, particularly those on toxicological mechanisms, are required to fully understand the nature of the "cadmium-AD mortality" association.

Associations of cumulative Pb exposure and longitudinal changes in Mini-Mental Status Exam scores, global cognition and domains of cognition: The VA Normative Aging Study.

BACKGROUND: Lead (Pb) exposure has been associated with poorer cognitive function cross-sectionally in aging adults, however the association between cumulative Pb exposure and longitudinal changes in cognition is little characterized. METHODS: In a 1993-2007 subcohort of the VA Normative Aging Study (Mini-mental status exam (MMSE) n=741; global cognition summary score n=715), we used linear mixed effects models to test associations between cumulative Pb exposure (patella or tibia bone Pb) and repeated measures of cognition (MMSE, individual cognitive tests, and global cognition summary). Cox proportional hazard modeling assessed the risk of an MMSE score falling below 25. RESULTS: Among men 51-98 at baseline, higher patella Pb concentration (IQR: 21µg/g) was associated with -0.13 lower baseline MMSE (95% CI: -0.25, -0.004) and faster longitudinal MMSE decline (-0.016 units/year, 95% CI: -0.032, -0.0004) over 15 years. Each IQR increase in patella Pb was associated with increased risk of a MMSE score below 25 (HR=1.21, 95% CI: 0.99, 1.49; p=0.07). There were no significant associations between Pb and global cognition (both baseline and longitudinal change). Patella Pb was associated with faster longitudinal decline in Word List Total Recall in the language domain (0.014 units/year, 95% CI: -0.026, -0.001) and Word List Delayed Recall in the memory domain (0.014 units/year, 95% CI: -0.027, -0.002). We found weaker associations with tibia Pb. CONCLUSIONS: Cumulative Pb exposure is associated with faster declines in MMSE and Word List Total and Delayed Recall tests. These findings support the hypothesis that Pb exposure accelerates cognitive aging.

Relationship between alcohol consumption and dementia with Mendelian randomization approaches among older adults in the United States.

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.

Improving prediction models of amyotrophic lateral sclerosis (ALS) using polygenic, pre-existing conditions, and survey-based risk scores in the UK Biobank.

Background and Objectives: Amyotrophic lateral sclerosis (ALS) causes profound impairments in neurological function and a cure for this devastating disease remains elusive. Early detection and risk stratification are crucial for timely intervention and improving patient outcomes. This study aimed to identify predisposing genetic, phenotypic, and exposure-related factors for Amyotrophic lateral sclerosis using multi-modal data and assess their joint predictive potential. Methods: Utilizing data from the UK Biobank, we analyzed an unrelated set of 292 ALS cases and 408,831 controls of European descent. Two polygenic risk scores (PRS) are constructed: "GWAS Hits PRS" and "PRS-CS," reflecting oligogenic and polygenic ALS risk profiles, respectively. Time-restricted phenome-wide association studies (PheWAS) were performed to identify pre-existing conditions increasing ALS risk, integrated into phenotypic risk scores (PheRS). A poly-exposure score ("PXS") captures the influence of environmental exposures measured through survey questionnaires. We evaluate the performance of these scores for predicting ALS incidence and stratifying risk, adjusting for baseline demographic covariates. Results: Both PRSs modestly predicted ALS diagnosis, but with increased predictive power when combined (covariate-adjusted receiver operating characteristic [AAUC] = 0.584 [0.525, 0.639]). PheRS incorporated diagnoses 1 year before ALS onset (PheRS1) modestly discriminated cases from controls (AAUC = 0.515 [0.472, 0.564]). The "PXS" did not significantly predict ALS. However, a model incorporating PRSs and PheRS1 improved prediction of ALS (AAUC = 0.604 [0.547, 0.667]), outperforming a model combining all risk scores. This combined risk score identified the top 10% of risk score distribution with a 4-fold higher ALS risk (95% CI: [2.04, 7.73]) versus those in the 40%-60% range. Discussions: By leveraging UK Biobank data, our study uncovers predisposing ALS factors, highlighting the improved effectiveness of multi-factorial prediction models to identify individuals at highest risk for ALS.

Alzheimer's Disease and Related Dementias in Muslim Women: Recommendations for Culturally Sensitive Care.

Alzheimer's disease and related dementias (ADRD) present significant challenges including cognitive and functional loss, behavioral disruption, emotional distress, and significant financial burden. These stressors are amplified in minority groups, who experience higher rates of ADRD but less frequent and later diagnosis. There is therefore a critical need to identify tangible approaches to culturally informed dementia assessment and care for patients from diverse communities. Muslim patients and particularly Muslim women are among the populations most understudied in the ADRD space. Muslim patients may hold unique religious, spiritual, and cultural beliefs and practices that can impact care-seeking for dementia symptoms, diagnostic accuracy, and treatment uptake. This paper outlines culturally informed approaches to assessing and treating Muslim women and families at each stage of ADRD care, though many recommendations extend to the broader Muslim community and others of diverse racial-ethnic backgrounds. We provide concrete suggestions for building rapport within and leveraging common family structures, respecting principles of modesty and privacy for all women including those who observe hijab or niqab, and communicating dementia diagnosis and care in the context of spiritual and ethical beliefs. While not intended as a comprehensive and prescriptive guide, this review provides important points of consideration and discussion with patients of Muslim backgrounds.

The mediating role of systemic inflammation and moderating role of racialization in disparities in incident dementia.

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 ( ≥ 75th 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.

Higher levels of inflammation in blood are linked to greater dementia risk in older adults. Non-Hispanic Black and Hispanic Americans have higher inflammation levels compared to non-Hispanic white Americans. We conducted a study to examine whether high levels of inflammation could explain differences in dementia risk among these racial groups. We found that differences in inflammation levels in non-Hispanic Black or Hispanic adults modestly explain their higher risk of dementia compared to non-Hispanic white adults. These findings suggest that interventions aimed at reducing high levels of inflammation in minoritized US adults could ameliorate racial differences in dementia risk.

Placental and Immune Cell DNA Methylation Reference Panel for Bulk Tissue Cell Composition Estimation in Epidemiological Studies.

To distinguish DNA methylation (DNAm) from cell proportion changes in whole placental tissue research, we developed a robust cell type-specific DNAm reference to estimate cell composition. We collated newly collected and existing cell type DNAm profiles quantified via Illumina EPIC or 450k microarrays. To estimate cell composition, we deconvoluted whole placental samples (n=36) with robust partial correlation based on the top 50 hyper- and hypomethylated sites per cell type. To test deconvolution performance, we evaluated RMSE in predicting principal component one of DNAm variation in 204 external placental samples. We analyzed DNAm profiles (n=368,435 sites) from 12 cell types: cytotrophoblasts (n=18), endothelial cells (n=19), Hofbauer cells (n=26), stromal cells (n=21), syncytiotrophoblasts (n=4), six lymphocyte types (n=36), and nucleated red blood cells (n=11). Median cell composition was consistent with placental biology: 60.4% syncytiotrophoblast, 17.1% stromal, 8.8% endothelial, 4.5% cytotrophoblast, 3.9% Hofbauer, 1.7% nucleated red blood cells, and 1.2% neutrophils. Our expanded reference outperformed an existing reference in predicting DNAm variation (15.4% variance explained, IQR=21.61) with cell composition estimates (RMSE:10.51 vs. 11.43, p-value<0.001). This cell type reference can robustly estimate cell composition from whole placental DNAm data to detect important cell types, reveal biological mechanisms, and improve casual inference.