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Integration of emerging epigenetic information with autism spectrum disorder (ASD) genetic results may elucidate functional insights not possible via either type of information in isolation. Here we use the genotype and DNA methylation (DNAm) data from cord blood and peripheral blood to identify SNPs associated with DNA methylation (meQTL lists). Additionally, we use publicly available fetal brain and lung meQTL lists to assess enrichment of ASD GWAS results for tissue-specific meQTLs. ASD-associated SNPs are enriched for fetal brain (OR = 3.55; P

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 (

Background: Common genetic variation has been shown to account for a large proportion of ASD heritability. Polygenic scores generated for autism spectrum disorder (ASD-PGS) using the most recent discovery data, however, explain less variance than expected, despite reporting significant associations with ASD and other ASD-related traits. Here, we investigate the extent to which information loss on the target study genome-wide microarray weakens the predictive power of the ASD-PGS. Methods: We studied genotype data from three cohorts of individuals with high familial liability for ASD: The Early Autism Risk Longitudinal Investigation (EARLI), Markers of Autism Risk in Babies-Learning Early Signs (MARBLES), and the Infant Brain Imaging Study (IBIS), and one population-based sample, Study to Explore Early Development Phase I (SEED I). Individuals were genotyped on different microarrays ranging from 1 to 5 million sites. Coverage of the top 88 genome-wide suggestive variants implicated in the discovery was evaluated in all four studies before quality control (QC), after QC, and after imputation. We then created a novel method to assess coverage on the resulting ASD-PGS by correlating a PGS informed by a comprehensive list of variants to a PGS informed with only the available variants. Results: Prior to imputations, None of the four cohorts directly or indirectly covered all 88 variants among the measured genotype data. After imputation, the two cohorts genotyped on 5-million arrays reached full coverage. Analysis of our novel metric showed generally high genome-wide coverage across all four studies, but a greater number of SNPs informing the ASD-PGS did not result in improved coverage according to our metric. Limitations. The studies we analyzed contained modest sample sizes. Our analyses included microarrays with more than 1-million sites, so smaller arrays such as Global Diversity and the PsychArray were not included. Our PGS metric for ASD is only generalizable to samples of European ancestries, though the coverage metric can be computed for traits that have sufficiently large-sized discovery findings in other ancestries. Conclusions: We show that commonly used genotyping microarrays have incomplete coverage for common ASD variants, and imputation cannot always recover lost information. Our novel metric provides an intuitive approach to reporting information loss in PGS and an alternative to reporting the total number of SNPs included in the PGS. While applied only to ASD here, this metric can easily be used with other traits. [ABSTRACT FROM AUTHOR]

Cord blood is widely used as surrogate tissue in epigenome-wide association studies of prenatal conditions. Cell type composition variation across samples can be an important confounder of epigenome-wide association studies in blood that constitute a mixture of cells. We evaluated a newly developed cord blood reference panel to impute cell type composition from DNA methylation levels, including nucleated red blood cells (nRBCs). We estimated cell type composition from 154 unique cord blood samples with available DNA methylation data as well as direct measurements of nucleated cell types. We observed high correlations between the estimated and measured composition for nRBCs (r = 0.92, R2 = 0.85), lymphocytes (r = 0.77, R2 = 0.58), and granulocytes (r = 0.72, R2 = 0.52), and a moderate correlation for monocytes (r = 0.51, R2 = 0.25) as well as relatively low root mean square errors from the residuals ranging from 1.4 to 5.4%. These results validate the use of the cord blood reference panel and highlight its utility and limitations for epidemiological studies.

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.

BackgroundEpigenetic mechanisms such as altered DNA methylation have been suggested to play a role in autism, beginning with the classical association of Prader-Willi syndrome, an imprinting disorder, with autistic features.ObjectivesHere we tested for the relationship of paternal sperm DNA methylation with autism risk in offspring, examining an enriched-risk cohort of fathers of autistic children.MethodsWe examined genome-wide DNA methylation (DNAm) in paternal semen biosamples obtained from an autism spectrum disorder (ASD) enriched-risk pregnancy cohort, the Early Autism Risk Longitudinal Investigation (EARLI) cohort, to estimate associations between sperm DNAm and prospective ASD development, using a 12-month ASD symptoms assessment, the Autism Observation Scale for Infants (AOSI). We analysed methylation data from 44 sperm samples run on the CHARM 3.0 array, which contains over 4 million probes (over 7 million CpG sites), including 30 samples also run on the Illumina Infinium HumanMethylation450 (450K) BeadChip platform (∼485 000 CpG sites). We also examined associated regions in an independent sample of post-mortem human brain ASD and control samples for which Illumina 450K DNA methylation data were available.ResultsUsing region-based statistical approaches, we identified 193 differentially methylated regions (DMRs) in paternal sperm with a family-wise empirical P-value [family-wise error rate (FWER)]

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. [ABSTRACT FROM AUTHOR]

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 β (Aβ)42, the Aβ42/40 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 Aβ42/40 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 Aβ42/40 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. [ABSTRACT FROM AUTHOR]

Background: The impact of knowledge of β‐amyloid status on cognitively unimpaired persons' cognitive test performance is unknown. Method: Cognitively unimpaired adults aged 65‐80 with a first‐degree relative with AD received a dementia risk estimate and were randomly assigned to disclosure (D+) or non‐disclosure (D‐) of their β‐amyloid PET scan result. At 6 weeks and 6 months post‐disclosure, participants completed the ADCS‐PACC, a composite of Free and Cued Selective Reminding (free portion), Logical Memory IIa test, Digit‐Symbol Substitution, and MMSE. Scores from each test are standardized to a Z‐score metric and a composite score calculated by summing the standardized Z‐scores. Result: 315 participants were randomized (84 elevated (41 A+D+/43 A+D‐)) and 231 not elevated (118 A‐D+, 113 A‐D‐)). After adjusting for baseline PACC scores, analyses compared PACC scores between (1.) A+D+ and A+D‐ and (2.) A‐D+ and A‐D‐ and stratified by race. A+ participants who learned their result (D+) had lower mean follow‐up PACC scores than participants who did not learn their β‐amyloid PET scan result (D‐) at 6 weeks (β = ‐0.89, 95% CI: ‐1.65, ‐0.13, p = 0.023) but not at 6 months post‐disclosure (β = ‐0.50, 95% CI ‐1.28, 0.27, p =.21). Mean follow‐up PACC scores did not differ between A‐ who did or did not learn their result at both 6 weeks (β ‐0.02, 95% CI: ‐0.42, 0.37, p = 0.91) and 6 months post‐disclosure (β ‐0.15, 95% CI ‐0.54, 0.25, p =.47). Analyses stratified by race showed Black/African American A+D+ had lower scores than A+D‐ at 6 weeks (β ‐2.01, 95% CI: ‐3.57, ‐0.45, p = 0.01) and 6 months post‐disclosure (β ‐1.63, 95% CI ‐3.19, ‐0.06, p =.04). Disclosure had no impact on scores of nonblack participants with elevated amyloid and the scores of any of not elevated participant groups. Conclusion: Knowledge of an elevated amyloid result reduced cognitively unimpaired persons PACC scores. A greater impact was observed in Black/African American participants' test performance compared to non‐Black participants. In contrast, knowledge of not‐elevated amyloid showed no impact on test performance in any of the groups. Clinical trials should consider the potential impact of AD biomarker knowledge on cognitive outcomes. [ABSTRACT FROM AUTHOR]