Next generation genome-wide association tool: Design and coverage of a high-throughput European-optimized SNP array

Hoffmann, Thomas J.; Kvale, Mark N.; Hesselson, Stephanie; Zhan, Yiping; Aquino, Christine; Cao, Yang; Cawley, Simon; Chung, Elaine; Connell, Sheryl; Eshragh, Jasmin L; Ewing, Marcia; Gollub, Jeremy; Henderson, Mary; Hubbell, Earl; Iribarren, Carlos; Kaufman, Jay S.; Lao, Richard; Lu, Yontao; Ludwig, Dana; Mathauda, Gurpreet K.; McGuire, William B.; Mei, Gangwu; Miles, Sunita; Purdy, Matthew M.; Quesenberry, Charles P.; Ranatunga, Dilrini K.; Rowell, Sarah; Sadler, Marianne; Shapero, Michael H.; Shen, Lei; Shenoy, Tanushree; Smethurst, David; Eeden, Stephen K. Van Den; Walter, Larry; Wan, Eunice; Wearley, Reid; Webster, Teresa A.; Wen, Christopher C.; Weng, Li; Whitmer, Rachel A.; Williams, Alan J.; Wong, Simon; Zau, Chia; Finn, Andrea; Schaefer, Catherine; Kwok, Pui‐Yan; Risch, Neil

doi:10.1016/j.ygeno.2011.04.005

Cited by 194 publications

(203 citation statements)

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“…A total of 102 998 samples were successfully assayed and passed genotyping quality control (QC). 19,20 The average age of the GERA cohort at the saliva sample collection was 62.9 (SD = 13.8) and had high KPNC membership retention (Supplementary Table 1). In this study, we focused on unrelated non-Hispanic white subjects in the GERA cohort who were at least 65 years of age as of 30 June 2013 (N = 53 449).…”

Section: Kaiser Permanente Gera Cohortmentioning

confidence: 99%

“…p1). 19,20 Samples with dish QC o0.82 or initial genotype call rateo0.97 were excluded, resulting in a total of 83 285 individuals of Europeans ancestry. 23 To improve genotype calls, SNPs were re-called within packages of plates assayed under similar conditions (array type, reagent, hybridization time, and DNA concentration).…”

Section: Genotyping Qc Imputation and Genetic Ancestry Of The Geramentioning

confidence: 99%

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Common coding variants in the HLA-DQB1 region confer susceptibility to age-related macular degeneration

et al. 2016

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Age-related macular degeneration (AMD) risk variants in the complement system point to the important role of immune response and inflammation in the pathogenesis of AMD. Although the human leukocyte antigen (HLA) region has a central role in regulating immune response, previous studies of genetic variation in HLA genes and AMD have been limited by sample size or incomplete coverage of the HLA region by first-generation genotyping arrays and imputation panels. Here, we conducted a large-scale HLA fine-mapping study with 4841 AMD cases and 23 790 controls of non-Hispanic white ancestry from the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohort. Genotyping was conducted using custom Affymetrix Axiom arrays, with dense coverage of the HLA region. Classic HLA polymorphisms were imputed using SNP2HLA, which utilizes a large reference panel to provide improved imputation accuracy of variants in this region. We examined a total of 6937 SNPs and 172 classical HLA alleles, conditioning on established AMD risk variants, which revealed novel associations with two non-synonymous SNPs in perfect linkage disequilibrium, rs9274390 and rs41563814 (odds ratio (OR) = 1.21; P = 1.4 × 10 − 11 ) corresponding to amino-acid changes at position 66 and 67 in HLA-DQB1, respectively, and the DQB1*02 classical HLA allele (OR = 1.22; P = 3.9 × 10 − 10 ) with the risk of AMD. We confirmed these association signals, again conditioning on established risk variants, in the MMAP data set of subjects with advanced AMD (rs9274390/rs41563814: OR = 1.28; P = 1.30 × 10 − 3 , DQB1*02: OR = 1.32; P = 9.00 × 10 − 4 ). These findings support a role of HLA class II alleles in the risk of AMD. European Journal of Human Genetics (2016) 24, 1049-1055; doi:10.1038/ejhg.2015.247; published online 6 January 2016 INTRODUCTION Age-related macular degeneration (AMD) is a complex, late-onset vision disorder, which is the leading cause of blindness among the elderly in developed countries. [1][2][3][4] Immune response and inflammation play a causal role in the pathogenesis and progression of AMD. [5][6][7][8][9][10][11] The human leukocyte antigen (HLA) region on chromosome 6p21.31 encodes gene products that regulate immune response. Drusen, a pathologic hallmark of AMD, contain HLA class II antigens, 12 and increased HLA class II immunoreactivity has been associated with drusen formation, 13 suggesting that HLA may influence the development of AMD. Although a few small candidate gene studies found that certain HLA class I and class II polymorphisms were associated with a predisposition to AMD, 14,15 the largest genome-wide association study (GWAS) meta-analysis conducted by the AMD Gene Consortium, which included more than 77 000 subjects, did not identify any HLA polymorphisms that were independently associated with the risk of AMD. 16 The AMD Consortium meta-analysis, although well powered to detect common variants of small effect, included a number of studies that utilized genotyping arrays, with array density ranging from 165 770 ...

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Section: Kaiser Permanente Gera Cohortmentioning

confidence: 99%

Section: Genotyping Qc Imputation and Genetic Ancestry Of The Geramentioning

confidence: 99%

Common coding variants in the HLA-DQB1 region confer susceptibility to age-related macular degeneration

et al. 2016

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“…To measure genetic ancestry, genomic DNA was first isolated from a blood specimen taken at the time of the initial study visit. Genome-wide genotyping was performed using the Axiom genome-wide AFR array (Affymetrix, Santa Clara, CA) on 1,040 SAPPHIRE subjects with asthma (20). We assessed local ancestry (i.e., African and European ancestry) at each autosomal single nucleotide polymorphism location (21,22), and we estimated the total percentage of African ancestry (i.e., global ancestry) in African American individuals as the proportion of African alleles.…”

Section: Measurement Of Nocturnal Asthma Symptoms and Accompanying Comentioning

confidence: 99%

Nocturnal Asthma and the Importance of Race/Ethnicity and Genetic Ancestry

Levin

Wang

Wells³

et al. 2014

Am J Respir Crit Care Med

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Rationale: Nocturnal asthma is a common presentation and is associated with a more severe form of the disease. However, there are few epidemiologic studies of nocturnal asthma, particularly in minority populations.Objectives: To identify factors associated with nocturnal asthma, including the contribution of self-identified race/ethnicity and genetic ancestry.Methods: The analysis included individuals from the Study for Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE) cohort. Nocturnal asthma symptoms were assessed by questionnaire. Genome-wide genotype data were used to estimate genetic ancestry in a subset of African American participants. Logistic regression was used evaluate the association of various factors with nocturnal asthma, such as self-identified race/ethnicity and genetic ancestry. Measurement and Main Results:The study comprised 3,380 African American and 1,818 European Americans individuals with asthma. After adjusting for other potential explanatory variables, including controller medication use, African Americans were more than twice as likely (odds ratio, 2.56; 95% confidence interval, 2.24-2.93) to report nocturnal asthma when compared with European American individuals. Among the subset of African American participants with genome-wide genotype data (n = 1,040), estimated proportion of African ancestry was also associated with an increased risk of nocturnal asthma (P = 0.007). Differences in lung function explained a small, but statistically significant (P = 0.02), proportion of the relationship between genetic ancestry and nocturnal asthma symptoms.Conclusions: Both self-identified race/ethnicity and African ancestry appear to be independent predictors of nocturnal asthma. The mechanism by which genetic ancestry contributes to populationlevel differences in nocturnal asthma appears to be largely independent of lung function.

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“…The original design of the Axiom arrays required probe sets for each SNP to be included at least twice for QC reasons. However, after initial experience with our first array for nonHispanic whites (Hoffmann et al 2011a), we expanded the number of SNPs on subsequent arrays by including some SNP probe sets only once, based on high-performance characteristics (Hoffmann et al 2011b). The four arrays were designed to maximize coverage in non-Hispanic whites (EUR), East Asians (EAS), African Americans (AFR), and Latinos (LAT).…”

Section: Axiom Platform Designmentioning

confidence: 99%

Genotyping Informatics and Quality Control for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort

et al. 2015

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The Kaiser Permanente (KP) Research Program on Genes, Environment and Health (RPGEH), in collaboration with the University of California-San Francisco, undertook genome-wide genotyping of .100,000 subjects that constitute the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. The project, which generated .70 billion genotypes, represents the first large-scale use of the Affymetrix Axiom Genotyping Solution. Because genotyping took place over a short 14-month period, creating a near-real-time analysis pipeline for experimental assay quality control and final optimized analyses was critical. Because of the multi-ethnic nature of the cohort, four different ethnic-specific arrays were employed to enhance genome-wide coverage. All assays were performed on DNA extracted from saliva samples. To improve sample call rates and significantly increase genotype concordance, we partitioned the cohort into disjoint packages of plates with similar assay contexts. Using strict QC criteria, the overall genotyping success rate was 103,067 of 109,837 samples assayed (93.8%), with a range of 92.1-95.4% for the four different arrays. Similarly, the SNP genotyping success rate ranged from 98.1 to 99.4% across the four arrays, the variation depending mostly on how many SNPs were included as single copy vs. double copy on a particular array. The high quality and large scale of genotype data created on this cohort, in conjunction with comprehensive longitudinal data from the KP electronic health records of participants, will enable a broad range of highly powered genome-wide association studies on a diversity of traits and conditions. KEYWORDS genome-wide genotyping; GERA cohort; Affymetrix Axiom; saliva DNA; quality control T HE Genetic Epidemiology Research on Adult Health and Aging (GERA) resource is a cohort of .100,000 subjects who are participants in the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC), Research Program on Genes, Environment and Health (RPGEH) (detailed description of the cohort and study design can be found in dbGaP, Study Accession: phs000674.v1.p1). Genome-wide genotyping was targeted for this cohort to enable large-scale genome-wide association studies by linkage to comprehensive longitudinal clinical data derived from extensive KPNC electronic health record databases. The cohort is multi-ethnic, with 20% minority representation (African American, East Asian, and Latino or mixed), and the remaining 80% nonHispanic white. For this project, four ethnic-specific arrays were designed based on the Affymetrix Axiom Genotyping System (Hoffmann et al. 2011a,b). The genotyping assay experiment took place over a 14-month period and to our knowledge, is the single largest genotyping experiment to date, producing .70 billion genotypes. The magnitude of the experiment, in conjunction with the long duration and simultaneous high throughput, required new protocols for assuring quality control (QC) during the assays and new genotyping strategies in postassay data analysis.Samp...

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Next generation genome-wide association tool: Design and coverage of a high-throughput European-optimized SNP array

Cited by 194 publications

References 27 publications

Common coding variants in the HLA-DQB1 region confer susceptibility to age-related macular degeneration

Common coding variants in the HLA-DQB1 region confer susceptibility to age-related macular degeneration

Nocturnal Asthma and the Importance of Race/Ethnicity and Genetic Ancestry

Genotyping Informatics and Quality Control for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort

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