Prepregnancy obesity is associated with lower psychomotor development scores in boys at age 3 in a low-income, minority birth cohort

Whether maternal obesity and gestational weight gain (GWG) are associated with early-childhood development in low-income, urban, minority populations, and whether effects differ by child sex remain unknown. This study examined the impact of prepregnancy BMI and GWG on early childhood neurodevelopment in the Columbia Center for Children's Environmental Health Mothers and Newborns study. Maternal prepregnancy weight was obtained by self-report, and GWG was assessed from participant medical charts. At child age 3 years, the Psychomotor Development Index (PDI) and Mental Development Index (MDI) of the Bayley Scales of Infant Intelligence were completed. Sex-stratified linear regression models assessed associations between prepregnancy BMI and pregnancy weight gain z-scores with child PDI and MDI scores, adjusting for covariates. Of 382 women, 48.2% were normal weight before pregnancy, 24.1% overweight, 23.0% obese, and 4.7% underweight. At 3 years, mean scores on the PDI and MDI were higher among girls compared to boys (PDI: 102.3 vs. 97.2, P = 0.0002; MDI: 92.8 vs. 88.3, P = 0.0001). In covariate-adjusted models, maternal obesity was markedly associated with lower PDI scores in boys [b = -7.81, 95% CI: (-13.08, -2.55), P = 0.004], but not girls. Maternal BMI was not associated with MDI in girls or boys, and GWG was not associated with PDI or MDI among either sex (all-P > 0.05). We found that prepregnancy obesity was associated with lower PDI scores at 3 years in boys, but not girls. The mechanisms underlying this sex-specific association remain unclear, but due to elevated obesity exposure in urban populations, further investigation is warranted

Prepregnancy obesity is associated with cognitive outcomes in boys in a low-income, multiethnic birth cohort

Background Maternal obesity and high gestational weight gain (GWG) disproportionally affect low-income populations and may be associated with child neurodevelopment in a sex-specific manner. We examined sex-specific associations between prepregnancy BMI, GWG, and child neurodevelopment at age 7. Methods Data are from a prospective low-income cohort of African American and Dominican women (n = 368; 44.8% male offspring) enrolled during the second half of pregnancy from 1998 to 2006. Neurodevelopment was measured using the Wechsler Intelligence Scale for Children (WISC-IV) at approximately child age 7. Linear regression estimated associations between prepregnancy BMI, GWG, and child outcomes, adjusting for race/ethnicity, marital status, gestational age at delivery, maternal education, maternal IQ and child age. Results Overweight affected 23.9% of mothers and obesity affected 22.6%. At age 7, full-scale IQ was higher among girls (99.7 ± 11.6) compared to boys (96.9 ± 13.3). Among boys, but not girls, prepregnancy overweight and obesity were associated with lower full-scale IQ scores [overweight β: − 7.1, 95% CI: (− 12.1, − 2.0); obesity β: − 5.7, 95% CI: (− 10.7, − 0.7)]. GWG was not associated with full-scale IQ in either sex. Conclusions Prepregnancy overweight and obesity were associated with lower IQ among boys, but not girls, at 7 years. These findings are important considering overweight and obesity prevalence and the long-term implications of early cognitive development

Phenotypic and molecular analyses of primary lateral sclerosis

Objective: To understand phenotypic and molecular characteristics of patients with clinically “definite” primary lateral sclerosis (PLS) in a prospective study. Methods: Six sites enrolled 41 patients who had pure upper motor neuron dysfunction, bulbar symptoms, a normal EMG done within 12 months of enrollment, and onset of symptoms ≥5 years before enrollment. For phenotypic analyses, 27 demographic, clinical, and cognitive variables were analyzed using the k-means clustering method. For molecular studies, 34 available DNA samples were tested for the C9ORF72 mutation, and exome sequencing was performed to exclude other neurologic diseases with known genetic cause. Results: K-means clustering using the 25 patients with complete datasets suggested that patients with PLS can be classified into 2 groups based on clinical variables, namely dysphagia, objective bulbar signs, and urinary urgency. Secondary analyses performed in all 41 patients and including only variables with complete data corroborated the results from the primary analysis. We found no evidence that neurocognitive variables are important in classifying patients with PLS. Molecular studies identified C9ORF72 expansion in one patient. Well-characterized pathogenic mutations were identified in SPG7, DCTN1, and PARK2. Most cases showed no known relevant mutations. Conclusions: Cluster analyses based on clinical variables indicated at least 2 subgroups of clinically definite PLS. Molecular analyses further identified 4 cases with mutations associated with amyotrophic lateral sclerosis, Parkinson disease, and possibly hereditary spastic paraplegia. Phenotypic and molecular characterization is the first step in investigating biological clues toward the definition of PLS. Further studies with larger numbers of patients are essential

Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS

BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 300,000 people worldwide. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms continue to develop, such as antisense oligonucleotides, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation.MethodsBuilding on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger multi-ethnic cohort of 6,970 ALS patients, 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS.ResultsA gene based collapsing model showed significant associations with SOD1, TARDBP, and TBK1 (OR = 19.18, p = 3.67 × 10–39; OR = 4.73, p = 2 × 10–10; OR = 2.3, p = 7.49 × 10–9, respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p = 4.88 × 10–7), was protective for ALS in this model. An intolerant domain-based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR = 10.08, p = 3.62 × 10–16). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p = 8.38 × 10–6).ConclusionsIn a large multi-ethnic cohort of 6,970 ALS patients, collapsing analyses validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2

Influence of Prenatal Arsenic Exposure and Newborn Sex on Global Methylation of Cord Blood DNA

Background An emerging body of evidence indicates that early-life arsenic (As) exposure may influence the trajectory of health outcomes later in life. However, the mechanisms underlying these observations are unknown. Objective The objective of this study was to investigate the influence of prenatal As exposure on global methylation of cord blood DNA in a study of mother/newborn pairs in Matlab, Bangladesh. Design Maternal and cord blood DNA were available from a convenience sample of 101 mother/newborn pairs. Measures of As exposure included maternal urinary As (uAs), maternal blood As (mbAs) and cord blood As (cbAs). Several measures of global DNA methylation were assessed, including the [3H]-methyl-incorporation assay and three Pyrosequencing assays: Alu, LINE-1 and LUMA. Results In the total sample, increasing quartiles of maternal uAs were associated with an increase in covariate-adjusted means of newborn global DNA methylation as measured by the [3H]-methyl-incorporation assay (quartile 1 (Q1) and Q2 vs. Q4; p = 0.06 and 0.04, respectively). Sex-specific linear regression analyses, while not reaching significance level of 0.05, indicated that the associations between As exposures and Alu, LINE-1 and LUMA were positive among male newborns (N = 58) but negative among female newborns (N = 43); tests for sex differences were borderline significant for the association of cbAs and mbAs with Alu (p = 0.05 and 0.09, respectively) and for the association between maternal uAs and LINE-1 (p = 0.07). Sex-specific correlations between maternal urinary creatinine and newborn methyl-incorporation, Alu and LINE-1 were also evident (p\u3c0.05). Conclusions These results suggest that prenatal As exposure is associated with global DNA methylation in cord blood DNA, possibly in a sex-specific manner. Arsenic-induced epigenetic modifications in utero may potentially influence disease outcomes later in life. Additional studies are needed to confirm these findings and to examine the persistence of DNA methylation marks over time

Long-Term Effects of Environmental Lead Exposure on Blood Pressure and Plasma Soluble Cell Adhesion Molecules in Young Adults: A Follow-Up Study of a Prospective Cohort in Kosovo

Background and Aims. Epidemiologic studies examining the relationship between environmental lead (Pb) exposure and blood pressure (BP) generally report small associations between blood lead concentration (BPb) and BP. However, these studies are predominantly cross-sectional. In addition, no epidemiologic studies evaluate associations between either current or past Pb exposure and serum levels of markers of systemic inflammation and endothelial dysfunction, including soluble vascular adhesion molecule (sVCAM-1) and soluble intercellular cell adhesion molecule (sICAM-1). We prospectively investigate these associations later in life. Methods. From our original prospective birth cohort study in Mitrovica (a mining town) and Prishtina (a control town), Kosovo, from 1985 to 1998, we located and assessed BPb and BP in 101 participants (mean age of 24.9 years old) in 2011. Results. We found highly statistically significant association between concurrent BPb and sVCAM-1 in men and a marginally significant association between concurrent PBb and sICAM.-1 in women. We did not find evidence of mediation. Conclusion. Current study results, along with previously reported findings on this cohort, provide evidence for the hypothesis that exposure to Pb leads to small increases in sBP and perhaps to increased circulating levels of sVCAM-1 and sICAM-1 later in life

Long-Term Effects of Environmental Lead on Erythropoietin Production in Young Adults: A Follow-Up Study of a Prospective Cohort in Kosovo

Background and Aims. Epidemiologic cross-sectional studies examining the relationship between environmental lead (Pb) exposure and erythropoietin (EPO) production have reported contrasting results. It is unknown, however, if exposure to Pb earlier in life has an effect on EPO production later in life. Here, using a prospective study, we evaluate the association between prenatal, early childhood, and concurrent Pb exposure and EPO concentration in young adulthood. Methods. From our prospective birth cohort study in Mitrovica (a mining town) and Pristina (a control town), Kosovo, from 1985 to 1998, we located and assessed blood lead concentration (BPb) and serum EPO in 101 participants (mean age 24.9 years) in 2011. We examined the association between BPb and EPO, stratified by hemoglobin (Hgb), and controlling for potential confounders. Results. These results resemble the findings in the original full cohort at 4.5 and 6.5 years of age, at which time we reported that the maintenance of a normal Hgb required increased EPO production among participants exposed to high levels of environmental Pb. In contrast, when the original cohort was 9.5 and 12 years of age, they were no longer capable of hyper-production of EPO in order to maintain normal levels of Hgb, suggestive of cumulative toxicity to the peritubular cells of the kidney that are responsible for EPO synthesis. Conclusion. Our results, along with previously reported findings on this cohort, suggest that a dramatic reduction of Pb exposure may allow for a reversal of the impact that prolonged Pb exposure may have on EPO production