Linkage analysis of urine arsenic species patterns in the Strong Heart Family Study

Matthew O. Gribble, Venkata Saroja Voruganti, Shelley A. Cole, Karin Haack, Poojitha Balakrishnan, Sandra L. Laston, Maria Tellez-Plaza, Kevin A. Francesconi, Walter Goessler, Jason G. Umans, Duncan C. Thomas, Frank Gilliland, Kari E. North, Nora Franceschini, Ana Navas-Acien

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Arsenic toxicokinetics are important for disease risks in exposed populations, but genetic determinants are not fully understood. We examined urine arsenic species patterns measured by HPLC-ICPMS among 2189 Strong Heart Study participants 18 years of age and older with data on ~400 genome-wide microsatellite markers spaced ~10 cM and arsenic speciation (683 participants from Arizona, 684 from Oklahoma, and 822 from North and South Dakota). We logit-transformed % arsenic species (% inorganic arsenic, %MMA, and %DMA) and also conducted principal component analyses of the logit % arsenic species. We used inverse-normalized residuals from multivariable-adjusted polygenic heritability analysis for multipoint variance components linkage analysis. We also examined the contribution of polymorphisms in the arsenic metabolism gene AS3MT via conditional linkage analysis. We localized a quantitative trait locus (QTL) on chromosome 10 (LOD 4.12 for %MMA, 4.65 for %DMA, and 4.84 for the first principal component of logit % arsenic species). This peak was partially but not fully explained by measured AS3MT variants. We also localized a QTL for the second principal component of logit % arsenic species on chromosome 5 (LOD 4.21) that was not evident from considering % arsenic species individually. Some other loci were suggestive or significant for 1 geographical area but not overall across all areas, indicating possible locus heterogeneity. This genome-wide linkage scan suggests genetic determinants of arsenic toxicokinetics to be identified by future fine-mapping, and illustrates the utility of principal component analysis as a novel approach that considers % arsenic species jointly.

Original languageEnglish (US)
Pages (from-to)89-100
Number of pages12
JournalToxicological Sciences
Issue number1
StatePublished - Nov 2015


  • Arsenic metabolism
  • Arsenic species
  • Linkage analysis
  • Strong Heart Family Study
  • Toxicogenetics
  • Toxicokinetics

ASJC Scopus subject areas

  • Toxicology


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