Design and implementation of a customized genotyping array for imputation-based genome-wide association studies: the Avera-NTR Global Screening Array

Prior to the inception of genome wide association studies (GWAS), the primary method for identifying causal genetic variants was through inheritance studies of genetic linkage. Single gene disorders have been well... [ view full abstract ]

Prior to the inception of genome wide association studies (GWAS), the primary method for identifying causal genetic variants was through inheritance studies of genetic linkage. Single gene disorders have been well characterized through linkage analyses; however, despite optimism about linkage designs for quantitative traits, the approach was not successful in studying human complex traits and diseases. With the increases in sample size, GWAS have gained utility as an informative and cost effective approach for identifying genetic variants associated with complex phenotypes. The fundamental method for generating data for GWAS is through high-density single nucleotide polymorphism (SNP) genotyping followed by imputation. The Avera Institute for Human Genetics has joined the Infinium Global Screening Array (GSA) Consortium initiated by Illumina, Inc., to gain access to a customized array containing highly predictive markers for translational research applications. In conjunction with collaborators at the Netherlands Twin Register (NTR), the Avera-NTR GSA array was designed to include a core imputation backbone and thousands of other markers of interest concerning Alzheimer’s disease, drug metabolism, fertility and twinning, and schizophrenia. Initial validation of the array was assessed by checking concordance, coverage, and imputation quality using the Genome of the Netherlands reference sequence. Preliminary application of the array was carried out with DNA extracted from a variety of tissues, including blood, buccal, and saliva samples. As of current, 10,484 samples (7,009 buccal, 3,056 blood, 419 saliva) have been genotyped on the Avera-NTR GSA array, with an overall weighted average call rate of 99.19% (99.04%, 99.60%, 98.66%, respectively) for 697,564 markers. In the future, investigative GWAS, for a multitude of human complex traits, including genetic variants associated with dizygotic twinning, will be conducted with the genotypic data generated by the Avera-NTR GSA array which has shown great utility in generating high-quality SNP data from multiple tissue types.