TitleGenome-wide gene by lead exposure interaction analysis identifies UNC5D as a candidate gene for neurodevelopment.
Publication TypeJournal Article
Year of Publication2017
AuthorsWang, Z, Henn, BClaus, Wang, C, Wei, Y, Su, L, Sun, R, Chen, H, Wagner, PJ, Lu, Q, Lin, X, Wright, R, Bellinger, D, Kile, ML, Mazumdar, M, Tellez-Rojo, MMaria, Schnaas, L, Christiani, DC
JournalEnviron Health
Date Published2017 Jul 28

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.

Alternate JournalEnviron Health
PubMed ID28754176
PubMed Central IDPMC5534076
Grant ListR00 ES022986 / ES / NIEHS NIH HHS / United States
P30 ES000002 / ES / NIEHS NIH HHS / United States
R01 ES007821 / ES / NIEHS NIH HHS / United States
R01 ES013744 / ES / NIEHS NIH HHS / United States
R01 ES014930 / ES / NIEHS NIH HHS / United States