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 βmeta = −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.
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We thank Maegan Harden, PhD, Broad Institute of MIT and Harvard, Boston, MA for assistance in genotyping the Bangladesh cohort. We thank Hakon Hakonarson, MD, PhD and Cecelia Kim, PhD, from the Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA for assistance in genotyping the Mexico cohort. This work was supported in part by National Institute of Environmental Health Sciences grants R01-ES007821, R01-ES014930, R01-ES013744, R01-ES022986, R01-ES015533, P42-ES016454, and P30-ES00002. Funding was also provided by Science to Achieve Results Research Assistance Agreement No. FP-91690001, awarded by the U.S. Environmental Protection Agency (EPA). The EPA has not officially endorsed this publication and the views expressed herein may not reflect the views of the EPA.
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