"Replicated" genome wide association for dependence on illegal substances: Genomic regions identified by overlapping clusters of nominally positive SNPs

Tomas Drgon, Catherine A. Johnson, Michelle Nino, Jana Drgonova, Donna M. Walther, George R. Uhl

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Declaring "replication" from results of genome wide association (GWA) studies is straightforward when major gene effects provide genome-wide significance for association of the same allele of the same SNP in each of multiple independent samples. However, such unambiguous replication may be unlikely when phenotypes display polygenic genetic architecture, allelic heterogeneity, locus heterogeneity, and when different samples display linkage disequilibria with different fine structures. We seek chromosomal regions that are tagged by clustered SNPs that display nominally significant association in each of several independent samples. This approach provides one "nontemplate" approach to identifying overall replication of groups of GWA results in the face of difficult genetic architectures. We apply this strategy to 1 million (1M) SNP Affymetrix and Illumina GWA results for dependence on illegal substances. This approach provides high confidence in rejecting the null hypothesis that chance alone accounts for the extent to which clustered, nominally significant SNPs from samples of the same racial/ethnic background identify the same chromosomal regions. There is more modest confidence in: (a) identification of individual chromosomal regions and genes and (b) overlap between results from samples of different racial/ethnic backgrounds. The strong overlap identified among the samples with similar racial/ethnic backgrounds, together with prior work that identified overlapping results in samples of different racial/ethnic backgrounds, support contributions to individual differences in vulnerability to addictions that come from both relatively older allelic variants that are common in many current human populations and newer allelic variants that are common in fewer current human populations.

Original languageEnglish (US)
Pages (from-to)125-138
Number of pages14
JournalAmerican Journal of Medical Genetics - Neuropsychiatric Genetics
Volume156
Issue number2
DOIs
StatePublished - Mar 2011
Externally publishedYes

Keywords

  • Microarray
  • Substance dependence

ASJC Scopus subject areas

  • Genetics(clinical)
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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