Practical Calling Approach for Exome Array-Based Genome-Wide Association Studies in Korean Population.

Exome-based genotyping arrays are cost-effective and have recently been used as alternative platforms to whole-exome sequencing. However, the automated clustering algorithm in an exome array has a genotype calling problem in accuracy for identifying rare and low-frequency variants. To address these shortcomings, we present a practical approach for accurate genotype calling using the Illumina Infinium HumanExome BeadChip.

Identification of a Systemic Lupus Erythematosus Risk Locus Spanning ATG16L2, FCHSD2, and P2RY2 in Koreans.

Objective: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder whose etiology is incompletely understood, but likely involves environmental triggers in genetically susceptible individuals. Using an unbiased genome-wide association (GWA) scan and replication analysis, we sought to identify the genetic loci associated with SLE in a Korean population.

Methods: A total of 1,174 SLE cases and 4,246 population controls from Korea were genotyped and analyzed with a GWA scan to identify single-nucleotide polymorphisms (SNPs) significantly associated with SLE, after strict quality control measures were applied.

On the Estimation of Heritability with Family-Based and Population-Based Samples.

For a family-based sample, the phenotypic variance-covariance matrix can be parameterized to include the variance of a polygenic effect that has then been estimated using a variance component analysis. However, with the advent of large-scale genomic data, the genetic relationship matrix (GRM) can be estimated and can be utilized to parameterize the variance of a polygenic effect for population-based samples. Therefore narrow sense heritability, which is both population and trait specific, can be estimated with both population- and family-based samples.

Influence of Genetic Variants in EGF and Other Genes on Hematological Traits in Korean Populations by a Genome-Wide Approach.

Hematological traits are important health indicators and are used as diagnostic clinical parameters for human disorders. Recently, genome-wide association studies (GWAS) identified many genetic loci associated with hematological traits in diverse ethnic groups. However, additional GWAS are necessary to elucidate the breadth of genetic variation and the underlying genetic architecture represented by hematological metrics.

A genome-wide association study of copy-number variation identifies putative loci associated with osteoarthritis in Koreans.

Background: OA is a complex disease caused by environmental and genetic risk factors. The purpose of this study is to identify candidate copy number variations (CNVs) associated with OA.

Methods: We performed a genome-wide association study of CNV to identify potential loci that confer susceptibility to or protection from OA.

Genome-wide association study identifies candidate Loci associated with platelet count in koreans.

Platelets are derived from the fragments that are formed from the cytoplasm of bone marrow megakaryocytes-small irregularly shaped anuclear cells. Platelets respond to vascular damage, contracts blood vessels, and attaches to the damaged region, thereby stopping bleeding, together with the action of blood coagulation factors. Platelet activation is known to affect genes associated with vascular risk factors, as well as with arteriosclerosis and myocardial infarction.

Combinatorial approach to estimate copy number genotype using whole-exome sequencing data.

Copy number variations (CNVs) are known risk factors in complex diseases. Array-based approaches have been widely used to detect CNVs, but limitations of array-based CNV detection methods, such as noisy signal and low resolution, have hindered detection of small CNVs. Recently, the development of next-generation sequencing techniques has increased rapidly owing to declines in cost.

Intake levels of dietary polyunsaturated fatty acids modify the association between the genetic variation in PCSK5 and HDL cholesterol.

Background: A low serum level of high-density lipoprotein cholesterol (HDL-C) is a risk factor for cardiovascular disease. Proprotein convertase subtilisin/kexin type 5 (PCSK5) modulates HDL-C metabolism through the inactivation of endothelial lipase activity.

Methods: Therefore, we analysed the effects of PCSK5 on HDL-C and investigated the association between genetic variation in PCSK5 and dietary polyunsaturated fatty acids (PUFAs) intakes in Korean adults and children.

Genome-wide association study identifies two novel Loci with sex-specific effects for type 2 diabetes mellitus and glycemic traits in a korean population.

Background: Until recently, genome-wide association study (GWAS)-based findings have provided a substantial genetic contribution to type 2 diabetes mellitus (T2DM) or related glycemic traits. However, identification of allelic heterogeneity and population-specific genetic variants under consideration of potential confounding factors will be very valuable for clinical applicability. To identify novel susceptibility loci for T2DM and glycemic traits, we performed a two-stage genetic association study in a Korean population.

Genome-wide association meta-analysis identifies novel variants associated with fasting plasma glucose in East Asians.

Fasting plasma glucose (FPG) has been recognized as an important indicator for the overall glycemic state preceding the onset of metabolic diseases. So far, most indentified genome-wide association loci for FPG were derived from populations with European ancestry, with a few exceptions. To extend a thorough catalog for FPG loci, we conducted meta-analyses of 13 genome-wide association studies in up to 24,740 nondiabetic subjects with East Asian ancestry.

New susceptibility loci in MYL2, C12orf51 and OAS1 associated with 1-h plasma glucose as predisposing risk factors for type 2 diabetes in the Korean population.

Most recently, 1-h hyperglycemia has been recognized as an additional risk factor for type 2 diabetes. To date, previous genome-wide association studies for glycemic traits have a limited impact on the fasting state and 2-h plasma glucose level in an oral glucose challenge. To identify genetic susceptibility in different stages of glucose tolerance, we performed a meta-analysis for glycemic traits including 1-h plasma glucose (1-hPG) from 14 232 non-diabetic individuals in the Korean population.

Meta-analysis identifies a MECOM gene as a novel predisposing factor of osteoporotic fracture.

Background: Osteoporotic fracture (OF) as a clinical endpoint is a major complication of osteoporosis. To screen for OF susceptibility genes, we performed a genome-wide association study and carried out de novo replication analysis of an East Asian population.

Methods: Association was tested using a logistic regression analysis.

Genotype instability during long-term subculture of lymphoblastoid cell lines.

Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) promise to address the challenge posed by the limited availability of primary cells needed as a source of genomic DNA for genetic studies. However, the genetic stability of LCLs following prolonged culture has never been rigorously investigated. To evaluate genotypic errors caused by EBV integration into human chromosomes, we isolated genomic DNA from human peripheral blood mononuclear cells and LCLs collected from 20 individuals and genotyped the DNA samples using the Affymetrix 500K SNP array set.

Gene-based copy number variation study reveals a microdeletion at 12q24 that influences height in the Korean population.

Height is a classic polygenic trait with high heritability (h(2)=0.8). Recent genome-wide association studies have revealed many independent loci associated with human height.

Replication of the Association of the 6q22.31c Locus near GJA1 with Pulse Rate in the Korean Population.

Pulse rate is known to be related to diverse phenotypes, such as cardiovascular diseases, lifespan, arrhythmia, hypertension, lipids, diabetes, and menopause. We have reported two genomewide significant genetic loci responsible for the variation in pulse rate as a part of the Korea Association Resource (KARE) project, the genomewide association study (GWAS) that was conducted with 352,228 single nucleoride polymorphisms typed in 8,842 subjects in the Korean population. GJA1 was implied as a functionally causal gene for pulse rate from the KARE study, but lacked evidence of replication.

Microarray-based mutation detection and phenotypic characterization in Korean patients with retinitis pigmentosa.

Purpose: To evaluate microarray-based genotyping technology for the detection of mutations responsible for retinitis pigmentosa (RP) and to perform phenotypic characterization of patients with pathogenic mutations.

Methods: DNA from 336 patients with RP and 360 controls was analyzed using the GoldenGate assay with microbeads containing 95 previously reported disease-associated mutations from 28 RP genes. Mutations identified by microarray-based genotyping were confirmed by direct sequencing.

A genome-wide association study identifies a breast cancer risk variant in ERBB4 at 2q34: results from the Seoul Breast Cancer Study.

Introduction: Although approximately 25 common genetic susceptibility loci have been identified to be independently associated with breast cancer risk through genome-wide association studies (GWAS), the genetic risk variants reported to date only explain a small fraction of the heritability of breast cancer. Furthermore, GWAS-identified loci were primarily identified in women of European descent.

Methods: To evaluate previously identified loci in Korean women and to identify additional novel breast cancer susceptibility variants, we conducted a three-stage GWAS that included 6,322 cases and 5,897 controls.

Large-scale genome-wide association studies in East Asians identify new genetic loci influencing metabolic traits.

To identify the genetic bases for nine metabolic traits, we conducted a meta-analysis combining Korean genome-wide association results from the KARE project (n = 8,842) and the HEXA shared control study (n = 3,703). We verified the associations of the loci selected from the discovery meta-analysis in the replication stage (30,395 individuals from the BioBank Japan genome-wide association study and individuals comprising the Health2 and Shanghai Jiao Tong University Diabetes cohorts). We identified ten genome-wide significant signals newly associated with traits from an overall meta-analysis.

Multilaboratory assessment of variations in spectrophotometry-based DNA quantity and purity indexes.

Human genetic studies are using an increasing number of biobanked DNA samples, which require consistent measurements of DNA quantity and purity between multicenters or multilaboratories. In an attempt to standardize DNA quantitation protocols, a DNA quantitation project was performed, in which 16 technicians from 11 laboratories participated in measuring optical density (A260, A280, A230) of multiple DNA samples (N = 35) of known concentrations. We analyzed variations in the measurement of DNA quantity and purity and found that the mean interoperator coefficients of variation percentage for A260, A260/A280, and A260/A230 values among individuals were 21.

Gene flow between the Korean peninsula and its neighboring countries.

SNP markers provide the primary data for population structure analysis. In this study, we employed whole-genome autosomal SNPs as a marker set (54,836 SNP markers) and tested their possible effects on genetic ancestry using 320 subjects covering 24 regional groups including Northern (=16) and Southern (=3) Asians, Amerindians (=1), and four HapMap populations (YRI, CEU, JPT, and CHB). Additionally, we evaluated the effectiveness and robustness of 50K autosomal SNPs with various clustering methods, along with their dependencies on recombination hotspots (RH), linkage disequilibrium (LD), missing calls and regional specific markers.

A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits.

To identify genetic factors influencing quantitative traits of biomedical importance, we conducted a genome-wide association study in 8,842 samples from population-based cohorts recruited in Korea. For height and body mass index, most variants detected overlapped those reported in European samples. For the other traits examined, replication of promising GWAS signals in 7,861 independent Korean samples identified six previously unknown loci.