title: Lack of association between autism and four heavy metal regulatory genes.
abstract: Autism is a common neurodevelopmental disorder with genetic and environmental components. Though unproven, genetic susceptibility to high mercury (Hg) body burden has been suggested as an autism risk factor in a subset of children. We hypothesized that exposure to "safe" Hg levels could be implicated in the etiology of autism if genetic susceptibility altered Hg's metabolism or intracellular compartmentalization. Genetic sequences of four genes implicated in the transport and response to Hg were screened for variation and association with autism. LAT1 and DMT1 function in Hg transport, and Hg exposure induces MTF1 and MT1a. We identified and characterized 74 variants in MT1a, DMT1, LAT1 and MTF1. Polymorphisms identified through screening 48 unrelated individuals from the general and autistic populations were evaluated for differences in allele frequencies using Fisher's exact test. Three variants with suggestive p-values <0.1 and four variants with significant p-values <0.05 were followed-up with TaqMan genotyping in a larger cohort of 204 patients and 323 control samples. The pedigree disequilibrium test was used to examine linkage and association. Analysis failed to show association with autism for any variant evaluated in both the initial screening set and the expanded cohort, suggesting that variations in the ability of the four genes studied to process and transport Hg may not play a significant role in the etiology of autism.
authors.affiliation: Department of Pediatric Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232-041, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Owens
authors.forename: Marshall L
authors.initials: ML
authors.lastname: Summar
authors.forename: Kelli K
authors.initials: KK
authors.lastname: Ryckman
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Sara
authors.initials: S
authors.lastname: Reiss
authors.forename: Samantha R
authors.initials: SR
authors.lastname: Summar
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
mesh_terms: D000293:Adolescent; D001321:Autistic Disorder / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D027283:Large Neutral Amino Acid-Transporter 1 / Q000235:genetics* / Q000378:metabolism; D015810:Linkage Disequilibrium; D008297:Male; D008628:Mercury / Q000378:metabolism*; D008668:Metallothionein / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011110:Polymorphism, Genetic; D018570:Risk Assessment; D012307:Risk Factors; D013714:Tennessee; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult; D000097809:Transcription Factor MTF-1; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D027283:Large Neutral Amino Acid-Transporter 1; D008628:Mercury; D008668:Metallothionein; D014157:Transcription Factors; D000097809:Transcription Factor MTF-1; D000099236:Solute Carrier Family 11, Member 2; C530099:MT1A protein, human