Integrative analysis of direct gene-gene interactions between GWIS genes and in vitro transcriptomic assay genes. (XLSX 18 kb

Birgit Claus Henn (4351825)

Chaolong Wang (140097)

David Bellinger (24603)

David Christiani (72443)

Han Chen (228557)

Li Su (71956)

Lourdes Schnaas (62668)

Maitreyi Mazumdar (3423881)

Martha Tellez-Rojo (4285639)

Molly Kile (71939)

Peter Wagner (577734)

Quan Lu (153192)

Robert Wright (587471)

Ryan Sun (4285636)

Xihong Lin (135298)

Yongyue Wei (391561)

Zhaoxi Wang (71954)

Environmental Health

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Additional file 9: Table S2. of Genome-wide gene by lead exposure interaction analysis identifies UNC5D as a candidate gene for neurodevelopment

Abstract 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

Zhaoxi Wang

Birgit Claus Henn

Chaolong Wang

Yongyue Wei

Li Su

Ryan Sun

Han Chen

Peter J. Wagner

Quan Lu

Xihong Lin

Robert Wright

David Bellinger

Molly Kile

Maitreyi Mazumdar

Martha Maria Tellez-Rojo

Lourdes Schnaas

David C. Christiani

Directory of Open Access Journals

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

Maltais, Danielle

Pouliot, Eve

Petit, Geneviève

Constellation

Le portrait des jeunes de la communauté de Lac-Mégantic

Functional annotation of GWIS genes. (XLSX 19 kb

Additional file 2: Table S1. of Genome-wide gene by lead exposure interaction analysis identifies UNC5D as a candidate gene for neurodevelopment

The stratified scatterplots show how the effect of Pb on Mental and Motor Composite Score is modified by the number of minor alleles at the two top SNPs. In particular, we can see how both scores appear to fall as Pb increases for subjects with no minor alleles (black symbols), but scores appear to rise as Pb increases for subjects with one minor alleles (blue symbols). This trend occurs for both SNPs and both outcomes, showing the significant interaction effect between the two SNPs and Pb concentration. (DOCX 169 kb

Additional file 4: Figure S3. of Genome-wide gene by lead exposure interaction analysis identifies UNC5D as a candidate gene for neurodevelopment

10.1186/s12940-017-0288-3Environmental Health: A Global Access Science Source1618

Wang, Z

Henn, B.C

Wang, C

Wei, Y

Su, L

Sun, R

Chen, H

Wagner, P.J

Lu, Q

Lin, X

Wright, R

Bellinger, D

Kile, M

Mazumdar, M

Tellez-Rojo, M.M

Schnaas, L

Christiani, D.C

ScholarBank@NUS

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. Electronic supplementary material The online version of this article (doi:10.1186/s12940-017-0288-3) contains supplementary material, which is available to authorized users

Wang, Zhaoxi

Henn, Birgit Claus

Wang, Chaolong

Wei, Yongyue

Su, Li

Sun, Ryan

Chen, Han

Wagner, Peter J.

Lu, Quan

Lin, Xihong

Wright, Robert

Bellinger, David

Kile, Molly

Mazumdar, Maitreyi

Tellez-Rojo, Martha Maria

Schnaas, Lourdes

Christiani, David C.

Harvard University - DASH 

https://figshare.com/articles/Additional_file_2_Table_S1_of_Genome-wide_gene_by_lead_exposure_interaction_analysis_identifies_UNC5D_as_a_candidate_gene_for_neurodevelopment/5258215

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Harvard University - DASH