Identification of novel loci associated with infant cognitive ability.

It is believed that genetic factors play a large role in the development of many cognitive and neurological processes; however, epidemiological evidence for the genetic basis of childhood neurodevelopment is very limited. Identification of the genetic polymorphisms associated with early-stage neurodevelopment will help elucidate biological mechanisms involved in neuro-behavior and provide a better understanding of the developing brain. To search for such variants, we performed a genome-wide association study (GWAS) for infant mental and motor ability at two years of age with mothers and children recruited from cohorts in Bangladesh and Mexico. Infant ability was assessed using mental and motor composite scores calculated with country-specific versions of the Bayley Scales of Infant Development. A missense variant (rs1055153) located in the gene WWTR1 reached genome-wide significance in association with mental composite score (meta-analysis effect size of minor allele ßmeta = -6.04; 95% CI: -8.13 to -3.94; P = 1.56×10-8). Infants carrying the minor allele reported substantially lower cognitive scores in both cohorts, and this variant is predicted to be in the top 0.3% of most deleterious substitutions in the human genome. Fine mapping and region-based association testing provided additional suggestive evidence that both WWTR1 and a second gene, LRP1B, were associated with infant cognitive ability. Comparisons with recently conducted GWAS in intelligence and educational attainment indicate that our phenotypes do not possess a high genetic correlation with either adolescent or adult cognitive traits, suggesting that infant neurological assessments should be treated as an independent outcome of interest. Additional functional studies and replication efforts in other cohorts may help uncover new biological pathways and genetic architectures that are crucial to the developing brain.

Maternal blood arsenic levels and associations with birth weight-for-gestational age.

BACKGROUND: Among highly exposed populations, arsenic exposure in utero may be associated with decreased birth weight, however less is known about potential effects of arsenic exposure in urban communities without contaminated sources such as drinking water. OBJECTIVE: Investigate the association of blood arsenic levels with birth weight-for-gestational age categories within a prospective birth cohort study. DESIGN/METHODS: We analyzed 730 mother-infant dyads within the Programming Research in Obesity, GRowth, Environment and Social Stressors (PROGRESS) cohort in Mexico City. Total arsenic was measured in maternal blood samples from the 2nd and 3rd trimesters, at delivery, as well as from infant umbilical cord blood samples. Multivariable, multinomial logistic regression models adjusting for maternal age at enrollment, pre-pregnancy body mass index, parity, infant sex, socioeconomic position, and prenatal environmental tobacco smoke exposure were used to calculate odds ratios of small-for-gestational age (<10th percentile, SGA) and large-for-gestational age (>90th percentile, LGA) compared to appropriate-for-gestational age (AGA) per unit increase of log-transformed arsenic. RESULTS: Median (IQR) blood arsenic levels for maternal second trimester were 0.72 (0.33) µg/L, maternal third trimester 0.75 (0.41) µg/L, maternal at delivery 0.85 (0.70) µg/L, and infant cord 0.78 (0.65) µg/L. Maternal delivery and infant cord blood samples were most strongly correlated (spearman r = 0.65, p < 0.0001). Maternal arsenic levels at delivery were associated with significantly higher odds of both SGA (adj. OR = 1.44, 95% CI: 1.08-1.93) and LGA (adj. OR = 2.03, 95% CI: 1.12-3.67) compared to AGA. Results were similar for cord blood. There were 130 SGA infants and 22 LGA infants. Earlier in pregnancy, there were no significant associations of arsenic and birth weight-for-gestational age. However, we observed non-significantly higher odds of LGA among women with higher arsenic levels in the 3rd trimester (adj. OR = 1.46, 95% CI: 0.67-3.12). CONCLUSION: We found that in a Mexico City birth cohort, higher maternal blood arsenic levels at delivery were associated with higher odds of both SGA and LGA. However, sources and species of arsenic were not known and the number of LGA infants was small, limiting the interpretation of this finding and highlighting the importance of future large studies to incorporate arsenic speciation. If our findings were confirmed in studies that addressed these limitations, determining modifiable factors that could be mitigated, such as sources of arsenic exposure, may be important for optimizing fetal growth to improve long-term health of children.

Bayesian varying coefficient kernel machine regression to assess neurodevelopmental trajectories associated with exposure to complex mixtures.

Exposure to environmental mixtures can exert wide-ranging effects on child neurodevelopment. However, there is a lack of statistical methods that can accommodate the complex exposure-response relationship between mixtures and neurodevelopment while simultaneously estimating neurodevelopmental trajectories. We introduce Bayesian varying coefficient kernel machine regression (BVCKMR), a hierarchical model that estimates how mixture exposures at a given time point are associated with health outcome trajectories. The BVCKMR flexibly captures the exposure-response relationship, incorporates prior knowledge, and accounts for potentially nonlinear and nonadditive effects of individual exposures. This model assesses the directionality and relative importance of a mixture component on health outcome trajectories and predicts health effects for unobserved exposure profiles. Using contour plots and cross-sectional plots, BVCKMR also provides information about interactions between complex mixture components. The BVCKMR is applied to a subset of data from PROGRESS, a prospective birth cohort study in Mexico city on exposure to metal mixtures and temporal changes in neurodevelopment. The mixture include metals such as manganese, arsenic, cobalt, chromium, cesium, copper, lead, cadmium, and antimony. Results from a subset of Programming Research in Obesity, Growth, Environment and Social Stressors data provide evidence of significant positive associations between second trimester exposure to copper and Bayley Scales of Infant and Toddler Development cognition score at 24 months, and cognitive trajectories across 6-24 months. We also detect an interaction effect between second trimester copper and lead exposures for cognition at 24 months. In summary, BVCKMR provides a framework for estimating neurodevelopmental trajectories associated with exposure to complex mixtures.

Lagged kernel machine regression for identifying time windows of susceptibility to exposures of complex mixtures.

The impact of neurotoxic chemical mixtures on children's health is a critical public health concern. It is well known that during early life, toxic exposures may impact cognitive function during critical time intervals of increased vulnerability, known as windows of susceptibility. Knowledge on time windows of susceptibility can help inform treatment and prevention strategies, as chemical mixtures may affect a developmental process that is operating at a specific life phase. There are several statistical challenges in estimating the health effects of time-varying exposures to multi-pollutant mixtures, such as: multi-collinearity among the exposures both within time points and across time points, and complex exposure-response relationships. To address these concerns, we develop a flexible statistical method, called lagged kernel machine regression (LKMR). LKMR identifies critical exposure windows of chemical mixtures, and accounts for complex non-linear and non-additive effects of the mixture at any given exposure window. Specifically, LKMR estimates how the effects of a mixture of exposures change with the exposure time window using a Bayesian formulation of a grouped, fused lasso penalty within a kernel machine regression (KMR) framework. A simulation study demonstrates the performance of LKMR under realistic exposure-response scenarios, and demonstrates large gains over approaches that consider each time window separately, particularly when serial correlation among the time-varying exposures is high. Furthermore, LKMR demonstrates gains over another approach that inputs all time-specific chemical concentrations together into a single KMR. We apply LKMR to estimate associations between neurodevelopment and metal mixtures in Early Life Exposures in Mexico and Neurotoxicology, a prospective cohort study of child health in Mexico City.

Uncovering neurodevelopmental windows of susceptibility to manganese exposure using dentine microspatial analyses.

BACKGROUND: Associations between manganese (Mn) and neurodevelopment may depend on dose and exposure timing, but most studies cannot measure exposure variability over time well. OBJECTIVE: We apply temporally informative tooth-matrix biomarkers to uncover windows of susceptibility in early life when Mn is associated with visual motor ability in childhood. We also explore effect modification by lead (Pb) and child sex. METHODS: Participants were drawn from the ELEMENT (Early Life Exposures in MExico and NeuroToxicology) longitudinal birth cohort studies. We reconstructed dose and timing of prenatal and early postnatal Mn and Pb exposures for 138 children by analyzing deciduous teeth using laser ablation-inductively coupled plasma-mass spectrometry. Neurodevelopment was assessed between 6 and 16 years of age using the Wide Range Assessment of Visual Motor Abilities (WRAVMA). Mn associations with total WRAVMA scores and subscales were estimated with multivariable generalized additive mixed models. We examined Mn interactions with Pb and child sex in stratified models. RESULTS: Levels of dentine Mn were highest in the second trimester and declined steeply over the prenatal period, with a slower rate of decline after birth. Mn was positively associated with visual spatial and total WRAVMA scores in the second trimester, among children with lower (< median) tooth Pb levels: one standard deviation (SD) increase in ln-transformed dentine Mn at 150 days before birth was associated with a 0.15 [95% CI: 0.04, 0.26] SD increase in total score. This positive association was not observed at high Pb levels. In contrast to the prenatal period, significant negative associations were found in the postnatal period from ~ 6 to 12 months of age, among boys only: one SD increase in ln-transformed dentine Mn was associated with a 0.11 [95% CI: - 0.001, - 0.22] to 0.16 [95% CI: - 0.04, - 0.28] SD decrease in visual spatial score. CONCLUSIONS: Using tooth-matrix biomarkers with fine scale temporal profiles of exposure, we found discrete developmental windows in which Mn was associated with visual-spatial abilities. Our results suggest that Mn associations are driven in large part by exposure timing, with beneficial effects found for prenatal levels and toxic effects found for postnatal levels.

Genome-wide gene by lead exposure interaction analysis identifies UNC5D as a candidate gene for neurodevelopment.

BACKGROUND: Neurodevelopment is a complex process involving both genetic and environmental factors. Prenatal exposure to lead (Pb) has been associated with lower performance on neurodevelopmental tests. Adverse neurodevelopmental outcomes are more frequent and/or more severe when toxic exposures interact with genetic susceptibility. METHODS: To explore possible loci associated with increased susceptibility to prenatal Pb exposure, we performed a genome-wide gene-environment interaction study (GWIS) in young children from Mexico (n = 390) and Bangladesh (n = 497). Prenatal Pb exposure was estimated by cord blood Pb concentration. Neurodevelopment was assessed using the Bayley Scales of Infant Development. RESULTS: We identified a locus on chromosome 8, containing UNC5D, and demonstrated evidence of its genome-wide significance with mental composite scores (rs9642758, p meta = 4.35 × 10-6). Within this locus, the joint effects of two independent single nucleotide polymorphisms (SNPs, rs9642758 and rs10503970) had a p-value of 4.38 × 10-9 for mental composite scores. Correlating GWIS results with in vitro transcriptomic profiles identified one common gene, SLC1A5, which is involved in synaptic function, neuronal development, and excitotoxicity. Further analysis revealed interconnected interactions that formed a large network of 52 genes enriched with oxidative stress genes and neurodevelopmental genes. CONCLUSIONS: Our findings suggest that certain genetic polymorphisms within/near genes relevant to neurodevelopment might modify the toxic effects of Pb exposure via oxidative stress.

Associations of iron metabolism genes with blood manganese levels: a population-based study with validation data from animal models.

BACKGROUND: Given mounting evidence for adverse effects from excess manganese exposure, it is critical to understand host factors, such as genetics, that affect manganese metabolism. METHODS: Archived blood samples, collected from 332 Mexican women at delivery, were analyzed for manganese. We evaluated associations of manganese with functional variants in three candidate iron metabolism genes: HFE [hemochromatosis], TF [transferrin], and ALAD [δ-aminolevulinic acid dehydratase]. We used a knockout mouse model to parallel our significant results as a novel method of validating the observed associations between genotype and blood manganese in our epidemiologic data. RESULTS: Percentage of participants carrying at least one copy of HFE C282Y, HFE H63D, TF P570S, and ALAD K59N variant alleles was 2.4%, 17.7%, 20.1%, and 6.4%, respectively. Percentage carrying at least one copy of either C282Y or H63D allele in HFE gene was 19.6%. Geometric mean (geometric standard deviation) manganese concentrations were 17.0 (1.5) µg/l. Women with any HFE variant allele had 12% lower blood manganese concentrations than women with no variant alleles (ß = -0.12 [95% CI = -0.23 to -0.01]). TF and ALAD variants were not significant predictors of blood manganese. In animal models, Hfe(-/-) mice displayed a significant reduction in blood manganese compared with Hfe(+/+) mice, replicating the altered manganese metabolism found in our human research. CONCLUSIONS: Our study suggests that genetic variants in iron metabolism genes may contribute to variability in manganese exposure by affecting manganese absorption, distribution, or excretion. Genetic background may be critical to consider in studies that rely on environmental manganese measurements.

Early postnatal blood manganese levels and children's neurodevelopment.

BACKGROUND: Recent evidence suggests that low-level environmental exposure to manganese adversely affects child growth and neurodevelopment. Previous studies have addressed the effects of prenatal exposure, but little is known about developmental effects of early postnatal exposure. METHODS: We studied 448 children born in Mexico City from 1997 through 2000, using a longitudinal study to investigate neurotoxic effects of early-life manganese exposure. Archived blood samples, collected from children at 12 and 24 months of age, were analyzed for manganese levels using inductively coupled plasma mass spectrometry. Mental and psychomotor development were scored using Bayley Scales of Infant Development at 6-month intervals between 12 and 36 months of age. RESULTS: At 12 months of age, the mean (SD) blood manganese level was 24.3 (4.5)microg/L and the median was 23.7 microg/L; at 24 months, these values were 21.1 (6.2) microg/L and 20.3 microg/L, respectively. Twelve- and 24-month manganese concentrations were correlated (Spearman correlation = 0.55) and levels declined over time ([beta] = -5.7 [95% CI = -6.2 to -5.1]). We observed an inverted U-shaped association between 12-month blood manganese and concurrent mental development scores (compared with the middle 3 manganese quintiles, for the lowest manganese quintile, [beta] = -3.3 [-6.0 to -0.7] and for the highest manganese quintile, [beta] = -2.8 [-5.5 to -0.2]). This 12-month manganese effect was apparent but diminished with mental development scores at later ages. The 24-month manganese levels were not associated with neurodevelopment. CONCLUSIONS: These results suggest a possible biphasic dose-response relationship between early-life manganese exposure at lower exposure levels and infant neurodevelopment. The data are consistent with manganese as both an essential nutrient and a toxicant.