AUTHOR=Wahlberg Karin E. , Guazzetti Stefano , Pineda Daniela , Larsson Susanna C. , Fedrighi Chiara , Cagna Giuseppa , Zoni Silvia , Placidi Donatella , Wright Robert O. , Smith Donald R. , Lucchini Roberto G. , Broberg Karin 

TITLE=Polymorphisms in Manganese Transporters SLC30A10 and SLC39A8 Are Associated With Children's Neurodevelopment by Influencing Manganese Homeostasis

JOURNAL=Frontiers in Genetics

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2018.00664

DOI=10.3389/fgene.2018.00664

ISSN=1664-8021

ABSTRACT=<p><bold>Background:</bold> Manganese (Mn) is an essential element but at excessive levels, it is neurotoxic. Even a moderate increase in Mn has been suggested to interfere with neurodevelopment in children. Genetics influencing Mn concentrations and toxicity is unclear.</p><p><bold>Objective:</bold> We assessed, in a cross-sectional study, whether common single-nucleotide polymorphisms in the Mn transporters SLC39A8 (influx) and SLC30A10 (efflux) are associated with neurodevelopment in children.</p><p><bold>Design:</bold> We genotyped <italic>SLC39A8</italic> (rs13107325 C/T) and <italic>SLC30A10</italic> (rs1776029 G/A and rs12064812 T/C) in Italian children (<italic>n</italic> = 686, ages 11–14). We then used linear regression models to analyze associations between genotype, blood Mn concentrations, and neurodevelopmental outcomes including intelligence, behavior, motor function, and sway. Inferred causal relationships were evaluated using instrumental variables (IV) analysis.</p><p><bold>Results:</bold> For <italic>SLC30A10</italic> rs1776029, the minor allele (A) was associated with increased average blood Mn of 41% (<italic>p</italic> &lt; 0.001), whereas minor alleles for rs12064812 (C) and rs13107325 (T) were associated with reduced blood Mn of 7% (<italic>p</italic> = 0.002) and 15% (<italic>p</italic> &lt; 0.001), respectively. For children carrying genotypes associated with high blood Mn, we observed lower performance for certain IQ subtests, increased sway, and increased scores for behavioral problems. High Mn genotypes showed odds ratios of 2–4 <italic>(p</italic> ≤ 0.01) for high scores in tests assessing ADHD-related behavior. IV analyses suggested that several of the associations were mediated by blood Mn.</p><p><bold>Conclusions:</bold> Our results suggest that common polymorphisms in <italic>SLC39A8</italic> and <italic>SLC30A10</italic> influence neurodevelopmental outcomes in children via differences in Mn homeostasis.</p>