Abstract
Misassigned alleles can annihilate efforts to control quality in otherwise well-designed genetic association analyses. To date, the issue remains underreported, as is exemplified by studies of a diallelic DRD2 missense variant in schizophrenia. For this variant, allele frequency data have been either misassigned, or incorrectly cited on four consecutive occasions. Contrary to conjecture, low heterozygosity has not guarded against the error with regard to rs1801028, a SNP that features a canonical base pair transversion, G:C. Measures are discussed that may help to identify misassigned alleles, and to avoid related perils pending more systematic investigation of this confounder in genotype-phenotype associations.
Highlights
Conflicting results in case-control association analyses are ascribed to many different factors, including significant phenotypic heterogeneity, population stratification artefacts, inadequate sample size, poorly matched control subjects, polygenic modes of inheritance, epigenetic factors, and multiple testing artefacts, to name only a few [1]
With the advent of haplotypic analyses, the scientific literature has experienced a surge in genetic association studies involving multiple diallelic markers and, at times, hundreds of SNPs [4]
Customized bioinformatic tools for the verification of batch SNP frequency data against the respective reference frequencies in specific ethnic groups are not currently available, and few reviewers are in a position to parse NCBI or other database data according to their needs
Summary
Conflicting results in case-control association analyses are ascribed to many different factors, including significant phenotypic heterogeneity, population stratification artefacts, inadequate sample size, poorly matched control subjects, polygenic modes of inheritance, epigenetic factors, and multiple testing artefacts, to name only a few [1]. With the advent of haplotypic analyses, the scientific literature has experienced a surge in genetic association studies involving multiple diallelic markers and, at times, hundreds of SNPs [4]. Core data of genetic association studies involving more than one or two markers may pass peer review essentially unscreened for correct allele assignment. Vijayan et al [2] have examined DRD2 alleles in schizophrenia, using the diallelic Taq1B (rs1079597), Taq1D (rs1800498), S311C (rs1801028), H313H (rs6275), and Taq1A (rs1800497) polymorphisms. To this avail, they have performed PCR-based restriction fragment length polymorphism assays, and have designed PCR primer pairs from alternating DNA strands. All 2-, 3-, 4- and 5-marker haplotypes inferred from rs1801028, are controversial
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