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The placenta mediates adverse pregnancy outcomes, including preeclampsia, which is characterized by gestational hypertension and proteinuria. Placental cell type heterogeneity in preeclampsia is not well-understood and limits mechanistic interpretation of bulk gene expression measures. We generated single-cell RNA-sequencing samples for integration with existing data to create the largest deconvolution reference of 19 fetal and 8 maternal cell types from placental villous tissue ( n  = 9 biological replicates) at term ( n  = 40,494 cells). We deconvoluted eight published microarray case–control studies of preeclampsia ( n  = 173 controls, 157 cases). Preeclampsia was associated with excess extravillous trophoblasts and fewer mesenchymal and Hofbauer cells. Adjustment for cellular composition reduced preeclampsia-associated differentially expressed genes (log 2 fold-change cutoff = 0.1, FDR < 0.05) from 1154 to 0, whereas downregulation of mitochondrial biogenesis, aerobic respiration, and ribosome biogenesis were robust to cell type adjustment, suggesting direct changes to these pathways. Cellular composition mediated a substantial proportion of the association between preeclampsia and FLT1 (37.8%, 95% CI [27.5%, 48.8%]), LEP (34.5%, 95% CI [26.0%, 44.9%]), and ENG (34.5%, 95% CI [25.0%, 45.3%]) overexpression. Our findings indicate substantial placental cellular heterogeneity in preeclampsia contributes to previously observed bulk gene expression differences. This deconvolution reference lays the groundwork for cellular heterogeneity-aware investigation into placental dysfunction and adverse birth outcomes. A single-cell RNA-seq analysis of placental villous tissue provides a deconvolution reference atlas of fetal and maternal placental cell types, and indicates that placental cellular heterogeneity in preeclampsia might contribute to differences in bulk gene expression.

Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurodegenerative disease with a median survival of only 2 to 4 years from diagnosis. Improved tools are needed to shorten diagnostic delays and improve prognostication to benefit clinical care. Herein, we profiled whole blood gene expression by RNA sequencing in a large cohort of ALS participants ( n  = 422) versus controls ( n  = 272). Several machine learning classifiers trained on our detailed gene expression dataset accurately predicted case-control status, including in a fully independent external test cohort, achieving an area under the receiver operating characteristic curve of 0.894 with the best performing model. Integrating gene expression features with clinical variables improved our ability to discriminate ALS cases into shorter, intermediate, and longer survival in an external dataset. Finally, we identified ALS-relevant pathways in our blood transcriptomics dataset as well as “core genes” that overlapped with gene expression changes occurring in the primary disease tissue, facilitating a drug perturbation analysis that identified several candidates. Overall, our results highlight the potential diagnostic and prognostic applications of whole blood gene expression data, with important implications for improving ALS clinical care. Zhao et al. generated models from whole blood gene expression to predict amyotrophic lateral sclerosis case-control status and combined gene features with clinical variables to predict survival, both validated in an external independent dataset.

BackgroundThe pathogenesis of amyotrophic lateral sclerosis (ALS) involves both genetic and environmental factors. This study investigates associations between metal measures in plasma and urine, ALS risk and survival and exposure sources.MethodsParticipants with and without ALS from Michigan provided plasma and urine samples for metal measurement via inductively coupled plasma mass spectrometry. ORs and HRs for each metal were computed using risk and survival models. Environmental risk scores (ERS) were created to evaluate the association between exposure mixtures and ALS risk and survival and exposure source. ALS (ALS-PGS) and metal (metal-PGS) polygenic risk scores were constructed from an independent genome-wide association study and relevant literature-selected single-nucleotide polymorphisms.ResultsPlasma and urine samples from 454 ALS and 294 control participants were analysed. Elevated levels of individual metals, including copper, selenium and zinc, significantly associated with ALS risk and survival. ERS representing metal mixtures strongly associated with ALS risk (plasma, OR=2.95, CI=2.38–3.62, p<0.001; urine, OR=3.10, CI=2.43–3.97, p<0.001) and poorer ALS survival (plasma, HR=1.37, CI=1.20–1.58, p<0.001; urine, HR=1.44, CI=1.23–1.67, p<0.001). Addition of the ALS-PGS or metal-PGS did not alter the significance of metals with ALS risk and survival. Occupations with high potential of metal exposure associated with elevated ERS. Additionally, occupational and non-occupational metal exposures were associated with measured plasma and urine metals.ConclusionMetals in plasma and urine associated with increased ALS risk and reduced survival, independent of genetic risk, and correlated with occupational and non-occupational metal exposures. These data underscore the significance of metal exposure in ALS risk and progression.

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.

Background Autism spectrum disorder (ASD) involves complex genetics interacting with the perinatal environment, complicating the discovery of common genetic risk. The epigenetic layer of DNA methylation shows dynamic developmental changes and molecular memory of in utero experiences, particularly in placenta, a fetal tissue discarded at birth. However, current array-based methods to identify novel ASD risk genes lack coverage of the most structurally and epigenetically variable regions of the human genome. Results We use whole genome bisulfite sequencing in placenta samples from prospective ASD studies to discover a previously uncharacterized ASD risk gene, LOC105373085 , renamed NHIP . Out of 134 differentially methylated regions associated with ASD in placental samples, a cluster at 22q13.33 corresponds to a 118-kb hypomethylated block that replicates in two additional cohorts. Within this locus, NHIP is functionally characterized as a nuclear peptide-encoding transcript with high expression in brain, and increased expression following neuronal differentiation or hypoxia, but decreased expression in ASD placenta and brain. NHIP overexpression increases cellular proliferation and alters expression of genes regulating synapses and neurogenesis, overlapping significantly with known ASD risk genes and NHIP -associated genes in ASD brain. A common structural variant disrupting the proximity of NHIP to a fetal brain enhancer is associated with NHIP expression and methylation levels and ASD risk, demonstrating a common genetic influence. Conclusions Together, these results identify and initially characterize a novel environmentally responsive ASD risk gene relevant to brain development in a hitherto under-characterized region of the human genome.

Background: Pregnancy measures of DNA methylation, an epigenetic mark, may be associated with autism spectrum disorder (ASD) development in children. Few ASD studies have considered prospective designs with DNA methylation measured in multiple tissues and tested overlap with ASD genetic risk loci. Objectives: To estimate associations between DNA methylation in maternal blood, cord blood, and placenta and later diagnosis of ASD, and to evaluate enrichment of ASD-associated DNA methylation for known ASD-associated genes. Methods: In the Early Autism Risk Longitudinal Investigation (EARLI), an ASD-enriched risk birth cohort, genome-scale maternal blood (early n = 140 and late n = 75 pregnancy), infant cord blood ( n = 133), and placenta (maternal n = 106 and fetal n = 107 compartments) DNA methylation was assessed on the Illumina 450k HumanMethylation array and compared to ASD diagnosis at 36 months of age. Differences in site-specific and global methylation were tested with ASD, as well as enrichment of single site associations for ASD risk genes ( n = 881) from the Simons Foundation Autism Research Initiative (SFARI) database. Results: No individual DNA methylation site was associated with ASD at genome-wide significance, however, individual DNA methylation sites nominally associated with ASD ( P < 0.05) in each tissue were highly enriched for SFARI genes (cord blood P = 7.9 × 10 –29 , maternal blood early pregnancy P = 6.1 × 10 –27 , maternal blood late pregnancy P = 2.8 × 10 –16 , maternal placenta P = 5.6 × 10 –15 , fetal placenta P = 1.3 × 10 –20 ). DNA methylation sites nominally associated with ASD across all five tissues overlapped at 144 (29.5%) SFARI genes. Conclusion: DNA methylation sites nominally associated with later ASD diagnosis in multiple tissues were enriched for ASD risk genes. Our multi-tissue study demonstrates the utility of examining DNA methylation prior to ASD diagnosis.

Trichloroethylene (TCE) is a volatile synthetic chemical used in various industrial processes like metal degreasing. Large amounts of TCE have been released into the environment. Exposure to TCE can occur through routes, such as inhalation for workers using TCE or ingestion of drinking water in contaminated areas. Macrophages are key immune cells in virtually all tissues in the human body, including the fetal membranes, making them a plausible target for DCVC-induced immunotoxicity. Macrophages are critical for maintaining anti-microbial defenses during pregnancy, but little data exists on TCE immunotoxicity during pregnancy. We previously showed that the TCE metabolite, -(1,2-dichlorovinyl)-L-cysteine (DCVC), down-regulates immune functions in fetal membranes. To gain insight into immune functions impacted by DCVC, we treated a macrophage cell model (THP-1 cells) with DCVC followed by stimulation with bacterial or fungal toxins relevant for intrauterine infections: lipopolysaccharide (LPS), lipoteichoic acid (LTA), or zymosan. DCVC inhibited toxin-stimulated release of cytokines (e.g. TNFα and IL-1β) for all three microbial toxins. We then conducted benchmark dose modeling and compared benchmark doses for DCVC cytotoxicity cytokine suppression and determined that inhibition of cytokine release was the more potent endpoint compared to cytotoxicity. Finally, we analyzed a previously generated transcriptomic dataset from THP-1 cells stimulated with LPS, with or without DCVC treatment. We identified transcription factors that were enriched with DCVC and/or LPS treatment, including NF-kB and Vitamin D receptor (VDR). Our findings show that DCVC potently alters cellular and molecular macrophage immune responses involved in defense against intrauterine pathogens.

We examined maternal prenatal vitamin use or supplemental folic acid intake during month one of pregnancy for association with autism spectrum disorder (ASD) in the Early Autism Risk Longitudinal Investigation, an enriched-risk pregnancy cohort. Total folic acid intake was calculated from monthly prenatal vitamins, multivitamins, and other supplement reports. Clinical assessments through age 3 years classified children as ASD (n = 38) or non-ASD (n = 153). In pregnancy month one, prenatal vitamin use (59.7%) was not significantly associated with odds of ASD (OR = 0.70, 95%CI 0.32, 1.53). Sample size was limited and residual confounding was possible. Given the estimated effect sizes in this and previous work, prenatal vitamin intake during early pregnancy could be a clinically useful preventative measure for ASD.

Background Prenatal vitamin use is recommended before and during pregnancies for normal fetal development. Prenatal vitamins do not have a standard formulation, but many contain calcium, folic acid, iodine, iron, omega-3 fatty acids, zinc, and vitamins A, B6, B12, and D, and usually they contain higher concentrations of folic acid and iron than regular multivitamins in the US Nutrient levels can impact epigenetic factors such as DNA methylation, but relationships between maternal prenatal vitamin use and DNA methylation have been relatively understudied. We examined use of prenatal vitamins in the first month of pregnancy in relation to cord blood and placenta DNA methylation in two prospective pregnancy cohorts: the Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk Learning Early Signs (MARBLES) studies. Results In placenta, prenatal vitamin intake was marginally associated with −0.52% (95% CI −1.04, 0.01) lower mean array-wide DNA methylation in EARLI, and associated with −0.60% (−1.08, −0.13) lower mean array-wide DNA methylation in MARBLES. There was little consistency in the associations between prenatal vitamin intake and single DNA methylation site effect estimates across cohorts and tissues, with only a few overlapping sites with correlated effect estimates. However, the single DNA methylation sites with p -value < 0.01 (EARLI cord n CpGs  = 4068, EARLI placenta n CpGs  = 3647, MARBLES cord n CpGs  = 4068, MARBLES placenta n CpGs  = 9563) were consistently enriched in neuronal developmental pathways. Conclusions Together, our findings suggest that prenatal vitamin intake in the first month of pregnancy may be related to lower placental global DNA methylation and related to DNA methylation in brain-related pathways in both placenta and cord blood.

Lead (Pb) exposure is associated with a wide range of neurological deficits. Environmental exposures may impact epigenetic changes, such as DNA methylation, and can affect neurodevelopmental outcomes over the life-course. Mating mice were obtained from a genetically invariant C57BL/6J background agouti viable yellow Avy strain. Virgin dams (a/a) were randomly assigned 0 ppm (control), 2.1 ppm (low), or 32 ppm (high) Pb-acetate water two weeks prior to mating with male mice (Avy/a), and this continued through weaning. At age 10 months, cortex neuronal nuclei were separated with NeuN+ antibodies in male mice to investigate neuron-specific genome-wide promoter DNA methylation using the Roche NimbleGen Mouse 3x720K CpG Island Promoter Array in nine pooled samples (three per dose). Several probes reached p-value < 10−5, all of which were hypomethylated: 12 for high Pb (minimum false discovery rate (FDR) = 0.16, largest intensity ratio difference = −2.1) and 7 for low Pb (minimum FDR = 0.56, largest intensity ratio difference = −2.2). Consistent with previous results in bulk tissue, we observed a weak association between early-life exposure to Pb and DNA hypomethylation, with some affected genes related to neurodevelopment or cognitive function. Although these analyses were limited to males, data indicate that non-dividing cells such as neurons can be carriers of long-term epigenetic changes induced in development.