Illumina human exome genotyping array clustering and quality control

Abstract

With the rise of high-throughput sequencing technology, traditional genotyping arrays are gradually being replaced by sequencing technology. Against this trend, Illumina has introduced an exome genotyping array that provides an alternative approach to sequencing, especially suited to large-scale genome-wide association studies (GWASs). the exome genotyping array targets the exome plus rare single-nucleotide polymorphisms (SNPs), a feature that makes it substantially more challenging to process than previous genotyping arrays that targeted common SNPs. Researchers have struggled to generate a reliable protocol for processing exome genotyping array data. The Vanderbilt epidemiology center, in cooperation with Vanderbilt Technologies for Advanced Genomics Analysis and Research Design (VANGARD), has developed a thorough exome chip–processing protocol. The protocol was developed during the processing of several large exome genotyping array-based studies, which included over 60,000 participants combined. The protocol described herein contains detailed clustering techniques and robust quality control procedures, and it can benefit future exome genotyping array–based GWASs.

Genetics: Implications for Prevention and Management of Coronary Artery Disease

“…Consequently, the study of very large sample sizes involving tens of thousands of individuals has been necessary to reliably identify novel associations involving rare variants uncovered through WES (144). Furthermore, it has been extremely challenging to examine rare variants individually (144).…”

“…Furthermore, it has been extremely challenging to examine rare variants individually (144). Instead, inference in WES studies have generally relied on comparing the aggregate number of rare variants within a gene observed among cases to that observed among controls (145).…”

Heterozygosity Ratio, a Robust Global Genomic Measure of Autozygosity and Its Association with Height and Disease Risk

“…The entire protocol for quality control and processing of the Exome chip data has been published (Guo et al 2014a). Briefly, quality control tests were conducted in Illumina Genome Studio and in PLINK (Purcell et al 2007).…”

“…All SNPs on the exome chip were converted to the HG19 reference genome forward strand. In PLINK, we quality controlled the BioVU data set for gender mismatches, relatedness, HWE, heterozygosity rate, and Mendelian error as stated in our protocol (Guo et al 2014a). In addition to BioVU Exome chip data, a second Exome chip data set of 10,906 (case N = 5852, control N = 5054) Chinese subjects from the Shanghai Breast Cancer Genetic Study (SBCGS) (Cai et al 2014) was used to test the association between heterozygosity ratio and height.…”

Exome-chip association analysis reveals an Asian-specific missense variant in PAX4 associated with type 2 diabetes in Chinese individuals

“…Genotype calling was conducted by GenTrain version 2.0 in GenomeStudio V2011.1 (Illumina). We first conducted manual inspection of genotype clusters for >55,000 variants that had either a GenTrain score <0.8, high missingness (>1%), or a poor genotype clustering, as determined by exome-chip genotyping of > 9000 individuals by collaborators [13,18]. A total of 4550 variants with poor genotype clustering were removed.…”